SI8411356A8 - Process for obtaining imidazolidinones and imidazolidintiones - Google Patents

Description

AMERICAN CYANAMID COMPANY

PROCEDURE FOR OBTAINING IMIDAZOLIDINONE AND IMIDAZOLIDINTION

FIELD OF THE INVENTION

The present invention falls within the field of organic chemistry, and more specifically relates to a process for the preparation of imidazolidinone and imidazolidintion.

According to the International Patent Classification, this invention is designated:

Technical problem

The present invention solves the problem of obtaining imidazolidinone and imidazolidinone by reducing Na-cyanoborohydride in the presence of a solvent.

v

The state of the art

This process yields new compounds that are unique in their structure as well as in their selective action on various undesirable plant species, thus exhibiting strong herbicidal properties.

- 2 Description of a technical problem

The present invention relates to a process for the preparation of imidazolidinone and imidazolidinone of formula (I):

%

X

Y -AA-COOR (I) wherein R is hydrogen; alkyl optionally substituted by one of the following groups: alkoxy, halogen, hydroxy, cycloalkyl, benzyloxy, furyl, phenyl, halophenyl, C 1 -C 4 alkylphenyl, C 1 -C 4 alkoxyphenyl, nitrophenyl, carboxy, alkoxycarbon - ··, cyano or a group of three (C 1 -C 1) alkylammonium; alkenes 1 for example substituted with one of the following groups: C 1 -C 4 alkoxy, phenyl, halogen, or C 1 -C 4 alkoxycarbonyl or with two C 1 -C 4 alkoxy and a moiety or two halogen atoms; A C 1 -C 4 cycloalkyl optionally substituted with a one or two C 1 -C 6 alkyl group; ^σ 3 ° 10 alkynyl; or, km, ion, such as alkali metals, alkaline earth metals, man-copper, iron, zinc, cobalt, lead, silver, nickel, ammonium. "" Organic ammonium;

R _{2 is} R ₂ each represents alkyl or cyclopropyl, under which the sum of the number of carbon atoms in R ₂ and R ₂ is 2 to 5; and code, - »

R 6 and R 8 together with the carbon to which they are attached form a cycloalkyl ring optionally substituted by a methyl group;

A is nitrogen or -CR2;

W is oxygen or sulfur;

X is hydrogen, halogen or methyl;

-2-3Description of a solution to a technical problem

The present invention relates to a process for the preparation of imidazolidinone and the imidazolidinone formula:

CH ₂ -C (C1) = CH ₂ , C _g H _{l 3} , CH (CH ₃ ) CH = CH-CH ₃ , CH ₂ CH = (CH ₃ ) ₂ , CH ₂ = CCH ₂ OH,

C (CH ₃ ) C 2 = CH, CH ₂ CH ₂ N® (CH ₃ ) ₃ I® -C (CH ₃ ) ₃ , '? 18 ^H 37' ^ 9 '

H_. CH ~ CH „OCH, C ^,

CH_-CH = CH-CH, -C 2 7 15

1225 '- ₂ ' - ₂ ™ 2''65 '~ 2

-CH ₂ -C3C _? H ₁₅ ,

CH_ - C = CH_, R. and R_ each before ^Z CH,

CH ₂ CH ₂ OCH ₃ ,

CH, CH = CH _n , -CH-CH = CH ,, CH, CHH.

put CH ₃ , CHiCH ^, C ^ H,., -Δ, CH ₂ Žh (CH ₃ ) ₂ , CHCHCCH ^, or together form -j ^ H-iCH ^ J -, - (CH ₂ ) - or - ( CH ^, A is nitrogen or CR ₃ where R _{3 is} hydrogen, X is H, CH ₃ , Cl, Y and 7. are each hydrogen, methyl, ocf ₃ , ch ₂ f, sch ₃ , ch ₂ «ch-ch ₂ o, c ₂ h ₅ , cf ₃ , c ₄ H _g , - ^^ - ci i ^Br »hQ-CH och ₃ , c ₃ h _? , ci, c ₆ h ₅ , cf ₃ , och ₂ -, ch = ch ₂ , oc ₆ h ₅ , n (ch ₃ ) ₂ , -och ₂ ch = ch ₂ , v

-OCH ₂ C = CH, -OCHF ₂ , OCH ₃ or together form - (CH ^ - or - (CH ^ -, and

- -3Υ and Su brother hydrogen, halogen, Cj-Cg alkyl, C - ^ - C ^ hydroxyalkyl, C -Ce ^a ^ alkoxy, θΐ "θ4 alkylthio, phenoxy, C ^ C ^ haloalkyl, OCF ₂ CHF ₂ , OCFj, OCHF ₂ , nitro, cyano, NR ^ R ^, C ^ -Cg of the normal series or branched alkenyloxy optionally substituted with one to three halogens, C ^ -Cg of the normal series or branched alkynyloxy optionally substituted with one to three halogens, or phenyl optionally substituted by one C 1 -C 4 and ^alkyl or C 1 -C 6 alkoxy group or halogen;

R 4 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, CF 4, NO ₂ , OCF ₅ , OCHF ₂ or OCF ₂ CHF ₂ ;

^R 4 is hydrogen or C 1 -C 6 alkyl;

R1 is alkyl;

and, when taken together, Ϊ and Z form a ring in which YZ is represented by (1) as: - (CH ₂ ) _n -, where not an integer is selected from 2, 3 and 4, provided that when A is -CR ^, then X is hydrogen;

or (2) with the structure: -C-C- <3 «C- where, when A is CRj, L, M, R?

LMR _? R 8 and R 8 each represent members selected from hydrogen, halogen, C 1 -C 6 alkyl and C 1 -C 4 alkoxy groups, and X is hydrogen; and when A is nitrogen, L, M, R? and R 8 each represents members selected from hydrogen, halogen, alkyl, C 1 -C 4 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfonyl, C 1 -C 4 haloalkyl, NO ₂ , CN, phenyl, phenoxy , amino, OCF ^, OCHF ₂ 0CF ₂ 0HF _2, Cj-C ^ alkylamino, dialkyl (C ^ -C ^) amino, chloro phenyl, methylphenyl, C -Ce Abnormal string or forked alkenyloxy Optionally substituted with up to three significa halogen, normal-chain C 1 -C 8 or branched alkynyloxy- optionally substituted with one to three halogens, or phenoxy substituted with one Cl, CF 4, NO ₂ or CH 4 group, provided that only one of L, M, R? or Rg may be a substituent that is different from hydrogen, halogen, θ1 * θ4 ^a - * - kil or a C1-C4 alkoxy group; or • 4W is O or S · The novelty of this process is that the compounds of the formula are reduced;

with sodium cyanoborohydride, in methanol, at room temperature

Particularly suitable compounds of the invention are further illustrated by Formulas II, III, IV, V, VI, VII and VIII.

2- (2-Imidazolidinyl) benzoic acid esters as well as salts of the present invention are represented by the formula II below:

(Π)

- 4a where R, R, R_, R_ X and W are as defined in the reference to the above formula 1, 1 & o except that when R is a cation, it is the same cation of alkali metals, alkaline earth metals, manganese, copper, iron, zinc, cobalt, lead, silver, nickel, ammonium or organic ammonium »Y and Z each independently represent members selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C4 alkylthio, nitro. C -C haloalkyl, OCF CHF, OCF OCHF, CN, -NR R,

X x i »6 * O t: □

C -C of a normal or branched chain alkenyloxy optionally substituted with one O o v

-5 to three halogens, a Oy-Cg normal series or a branched alkynyloxy opcinone substituted with one to three halogens, or phenyl optionally substituted by one O-C 0 -C 6 alkyl, C 1 -C 6 alkoxy group or halogen; R 4 is hydrogen or C 1 -C 4 alkyl; R 2 is C 1 -C 4. alkyl; · And when taken together, Y and Z can form a ring in which YZ is represented by the structure: - (CH ₂ ) _n -, where not an integer is selected from 2, 3 and 4, and X is hydrogen ;, or by the structure: LM RrjRg »where M»

-C &apos; CC &apos; CRp, and R8 each represent members selected from hydrogen, halogen, C1-6alkyl and O1-G1 alkoxy groups; i bath R and R ₂ pets not the same, optical and cis- and trans-isomers of the same and except that when r is a cation, and their addition salts with acids.

Suitable 2- (2-imidazolidinyl) nicotinic acid esters as well as salts of the present invention are given by Formula XII below:

where R, Rp are R ₂ , WIX as defined in the reference to Formula I above, except that when R is a cation, the same is a cation of alkali metals, alkaline earth metals, manganese, copper, iron, zinc, cobalt, lead, silver , nickel, ammonium or organic ammonium cation, Y and Z each independently represent members selected from the group consisting of hydrogen, halogen, Ο-ρ-Οθ alkyl, Ο ^ -Οθ alkoxy, ON, N0 ₂ , 0C? ₅ , OCHP ₂ , 9CF ₂ OHF ₂ , phenoxy, 0 _χ- O ₄ haloalkyl, alkylthio, C 1 -C 4 hydroxyalkyl, NR 4 R 4, C 0 -Og of the normal series or branched alkenyloxy optionally substituted by one to three halogens. A C ₅ -Οθ normal sequence or a branched alkynyloxy opcinone substituted with one to three halogens, or phenyl opcinone substituted-6san with one C 1 -C 4 alkyl 'C 1 -C 6 alkoxy group or halogen;

R1 is hydrogen or alkyl; R1 is alkyl; and when taken together Y and Z may form a ring in which YZ is represented by the structure: - (CH ₂ ) _n -, where n is an integer selected from 2, 5 and 4 ·} and when R ^ and R _{2 are} not the same »optical and cis- and trans-isomers thereof, except when R is a cation, their addition salts with acids.

The esters and salts of 2- (2-imidazolidinyl) quinoline-3-carboxylic acids according to the present invention are given by the formula IV below:

• 8

where R, Rp are R ₂ W and X as defined above in the reference to Formula I, except that when R is a cation, it is the same cation of alkali metals, alkaline earth metals, manganese, copper, iron, zinc, cobalt, lead , silver, nickel, cation ammonium or organic ammonium, and L, M, R? and R 8 represent members selected from the group consisting of hydrogen, halogen, alkyl, O-4-alkoxy, O-4-alkylthio, C 1 -C 4 -alkylsulfonyl, O-haloalkyl, NOg, -CN., phenyl, ₂ . CJ-C4 alkylamino, dialkyl · phenoxy, amino, CP ^ 0CHP ₂ 0CP ₂ CHP amino hlorfenil, methylphenyl, CyCg Abnormal string or forked alkenyloxy opeiono substituted with significa to three halogen, C ₅ -C ₈ Abnormal string or forked alkynyloxy optionally substituted with one to three halogens, or phenoxy substituted with one Cl, CP ^, NO ₂ or CH ^ group, provided that only one of L, M, R? and R 8 may be a substituent other than hydrogen, halogen, C 1 -C 6 alkyl or C 1 -C 4 alkoxy; and when R ^ and R _{2 are} not

7ists, their optical and cis- and trans-isomers, except when R is a cation, their addition salts with acids.

Esters and salts of 2- (2-imidazolidinyl) thieno- and furoC3,2-b] pyridine-6-carboxylic acids and esters and salts of 2- (2-imidazolidinyl) -2,3-dihydrothieno- and furo [3i2-b] pyridine-6 -carboxylic acids according to the present invention are represented by formulas V and VI which are further given:

wherein R, R ^, R ₂ , W and B are as defined above in the reference to formula I, except that when R is a cation, it is the same cation of alkali metals, alkaline earth metals, manganese, cobalt, iron, zinc, cobalt, lead, silver, nickel, ammonium cation or organic ammonium cation; R 2 and R 4 each represent a member selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl and phenyl; and R and R _{12 lx} brother represents hydrogen, C? alkyl or phenyl; i bath R and R ₂ pets not the same, optical and cis- and trans-isomers of the same and except that when r is a cation, and their addition salts with acids.

Esters and salts of 2- (2-imidazolidinyl) thieno- and furo [2,3-b] pyridine-5-carbonic acids and esters and salts of 2- (2-imidazolidinyl) -2,3-dihydrothieno- and furo [2,3-b The pyridine-5-carboxylic acids of the present invention are given by Formulas VII and VIII below:

-δ-

ίνη) (VIII) where R, Rp are R ^ W and B as defined above in the reference to formula I, except that when R is a cation, it is the same cation of alkali metals, alkaline earth metals, manganese, copper, iron, zinc. cobalt, lead, silver, nickel, ammonium and organic ammonium, Rg and

R 2 each represents a member selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl and phenyl; R p and R ₁₂ each represent a member selected from the group consisting of hydrogen, C 1 -C 4 alkyl and phenyl; and when R ^ and R _{2 are} not the same, their optical ethers and except when R is a cation, their addition salts with acids.

In this specification and the Requirements, alkali metals include: sodium, potassium and lithium, although sodium is generally preferred. Also, in this specification and the Requirements, unless otherwise indicated, the term organic ammonium is defined as a group containing positively charged nitrogen atoms linked to form up to four aliphatic groups, each containing from one to 20 carbon atoms., Of organic ammonium groups which su illustrative of preparing aliphatic ammoniac salts imidazolidinyl acid formula I to VIII su: monoalkilamonijum, dialkilamonijum, trialkilamonijum, tetraalkilamonijum, monoalkenilamonijum, dialkilenamonijum, trialkenilamonijum, monoalkinilM * ammonium, dialkinilamonijum, trialkinilamonijum, monoalkanolamonijum, dialkanolamonijum, trialkanolamonijum C ^ -Οθ cikloalkilamonijum, piperinium , porpholinium, pyrrolidinium, benzylammonium and their equivalents.

-9As stated above, the present invention relates to imidazolidinone and imidazolidinethione compounds represented by formula I, a process and intermediates for the preparation thereof and a method for combating a wide variety and types of undesirable monocotyledonous and dicotyledonous plant species. This formula I, which represents the compounds of the present invention, is a compound that is unique both in its chemical structure and in its herbicidal activity. Although imidazolinyl benzoic acid esters and salts have been described as herbicidal agents in U.S. Pat. Patent no. 4.188.487. from. February 20, 1980, and imidazolinyl pyridines and quinolines were described as herbicidal agents in European patent application no. 81103638.3, the aforementioned publications do not clearly state that the compounds neither have imidazolidinyl function nor provide a process by which the compounds may be obtained. Moreover, it has been safely found that the compounds of formula I according to this invention are highly selective and / or have different efficacy in terms of activity as herbicides without affecting the crops to which they are applied, all with respect to said imidazolinyl compounds.

Many substituted and unsubstituted aromatic and heteroaromatic imidazolidinone and imidazolidinone compounds represented by formula I can be obtained by reducing the corresponding imidazolinone or imidazolinethione with, for example, at least about an equimolar amount of sodium cyanoborohydride in the presence of an alcohol or solubiliser acidification is carried out to a pH of between about 2.5 and 5, and preferably between 3 and 4, with a strong mineral acid such as hydrochloric acid or an organic acid such as acetic or similar acid. This reduction is ge-10nerally done at a temperature between O and 4O ° C, and is especially effective for treating 2- (2-imidazolinyl) nicotinic acids and esters, but best of esters · Reduction is similarly effective for reducing the imidazolinyl function of many imidazolinyl benzoic acids and esters. The process is similarly effective for reducing the imidazolinyl function of the compounds of formula V and VI 2- (2-imidazolinyl) thieno and furo [3,2-b] pyridine-6-carboxylic acid esters and the compounds of formula VII and VIII 2- (2- imidazolinyl) thieno and esters of furo [2,3-b] · pyridine-5-carboxylic acid esters; but is ineffective in reducing the imidazolinyl function of 2- (2-imidazolinyl) quinoline-5-carboxylic acid esters.

The reduction described above can be graphically illustrated as follows:

wherein R may be hydrogen, but the optionally substituted or unsubstituted alkyl, alkenyl, alkynyl or cycloalkyl group as defined above in the reference to formula I and R p R 4, V /, X, Y, Z, and A are as defined in the reference to the aforementioned formula I, except that when A is -0R ^, R ^ cannot be fluorine.

As shown above, imidazolidinones and imidazolidinones are obtained as mixtures of -cis- and trans-isomers when 10 and 10 are not the same. These isomers are digested in different mols. The mixtures are useful as such, but can usually be separated by chromatography to give a pure cis- and trans-isomer, both of which are effective

-11 as herbicidal agents.

As the reduction described above is not a universal method with the preparation of all substituted and unsubstituted aromatic and heteroaromatic imidazolidinones and imidazolidintion of the forms given,

effective methods for the preparation of the compounds of formula I imidazolidinone and imidazolidinone.

The reaction of an aldehyde of formula (X) with an amide of formula (IX) under acid catalysis is assumed, and the corresponding Schiff base is obtained as the starting product. If Schiff's base is of the general formula

X

Isolates as such or cyclizes under the reaction conditions to the desired imidazelidinone depends on some unknown barely noticeable factors. Nevertheless, if Schiff's base is isolated, it can be cyclized with trifluoroacetic acid to imidazolidinone in a special reaction.

According to Torn, it has now been determined that thioxo derivatives of the formula

II 2- (2-Imidazolidinyl) benzoates and oxo and thioxo derivatives of the formula

III 2- (2rimidazolidinyl) nicotinates and Formulas IV 2- (2-imidazolidinyl) quinoline-3-carboxylates can be synthesized by refluxing, a mixture of a compound of formula IX aminoamide or aminothioamide with about an equimolar amount of a suitable compound of formula X substituted or unsubstituted alkyl, substituted or unsubstituted alkyl , alkynyl or cycloalkyl 2-formylbenzoate, 2-formylpyridine-3-carboxylate, or

-122-formylquinoline-3-carboxylate, in the presence of an inert organic solvent such as benzene, toluene, or the like, and strong organic acids such as p-toluenesulfonic acid (p-TSA), in a nitrogen stream. These reactions can be represented graphically as follows:

wherein R is a substituted or unsubstituted alkyl, alkenyl, alkynyl, or cycloalkyl radical as defined in the reference to formula I, and A, R ₂ , R ₂ , R 4, W, X, Y and Z are all defined in the reference to said formula I, provided that (1) when A is -CR ^, W is S; and (2) when taken together, Y and Z form a ring in which YZ is represented by (a) the structure: - (CH ₂ ) _n - ^{n an integer} of

2, 3 and 4, where R ^ and X are each hydrogen; or (b) the structure of the LMR? where L, M, R? and R8 each represents members of the group ^C 5-10Su 2acTSaAva are hydrogen, halogen, C 1 -C 4 alkyl and C 1 -C 4 alkoxy and R 1 and X are each hydrogen.

Although the above procedure is effective for the synthesis of thioxo derivatives of formula II 2- (2-imidazolidinyl) benzoate and oxo and thioxo derivatives of 2- (2-imidazolidinyl) nicotinate and quinoline-3-carboxylate of formula III and TV, for the preparation of oxo derivatives of formula II 2 - (2-Imidazolidinyl) benzoates certain modifications are required.

-15To obtain oxo derivatives of formula II 2- (2-imidazolidinyl) benzoate, it has been found that approximately equimolar amounts of the compounds of formula XI substituted or unsubstituted alkyl, alkenyl, alkynyl or cycloalkyl 2-formylbenzoate and compounds of formula XII the aminoamide can be mixed together the presence of an organic acid such as p-toluenesulfonic acid and an aromatic solvent such as toluene, xylene or the like, to give the Schiff base represented by formula XIII. This Schiff base of formula XIII is then elicited by its treatment with trifluoroacetic acid in the presence of chlorinated hydrocarbon as a growth cheater, such as methylene chloride. The reaction is best carried out under a stream of nitrogen at a temperature between about -5 and + 5 ° C. The reaction yields a mixture of cis- and trans-isomers of formula XIV oxo-2-imidazolidinyl benzoate. The reaction can be represented as follows:

14—

R3 (XI)? Ι nh ₂ —γ — conh ₂ R2

CH ₂ C1 ₂

Trifluoroacetic acid

Cis

Trans (XIV)

-15Conversion of esters of formula I imidazolidinone and imidazolidinethione into their corresponding acid addition salts is readily accomplished by dispersing or dissolving the compounds of the formula I ester of imidazolidinone and ester imidazolidinethione in an organic solvent such as methylene chloride, chloroform, ether, or C 1-6 alcohol or C 1-6 alcohol or , and by treating the mixture thus obtained with at least an equivalent, and preferably at excess, strong acid, especially strong mineral acid, such as hydrochloric acid, sulfuric acid, hydrobromic acid, or the like. The solvent was then removed in vacuo and the residue was crystallized from a mixture of organic solvents such as ethyl acetate and ether to give the corresponding addition salt with an acid of formula I.

Kao further ostvarenje axle ovom the invention, the compounds of formula I, those in which R is hydrogen, and R, R _2, R, W, X, Y, Z and A su such as a progressive defined above, can be prepared by dissolving or dispergovanjem compounds of the imidazolidinone ester and imidazolidinone ester of the C 1 -C 4 aliphatic alcohol, preferably in absolute methanol, and mixing them with at least one equivalent of a strong base. In practice, the base dissolves in water and the mixture is heated to between about 20 and 50 ° θ · The mixture is then cooled and the pH adjusted to pH 6.5 to 7 »5» and preferably about pH 7 · with a strong mineral acid such as hydrochloric acid to give imidazolidinone or imidazolidinethion of formula I in which R is hydrogen and R ₂ , R ₂ , R 4, W, X, Y, Z and A are as defined for the compounds of formula I. The reaction can be illustrate as follows:

1. CH, OH / NaOH

-? -: - γ

2. Acid

where B is other than hydrogen or a ^{cationic salt} formed, and Rp ^ 2 ' ^X ' ^{Z are} ^ ^{a0 št0} d ^e opi ^with n ° ^{in the} reference to formula I,

Compounds of formula I in which R is a cationic salt such as an alkali metal or alkaline earth metal salt, and R1, R8, W, X, Y, Z and A are as defined for formula I, can be obtained by dissolving the formed salt with a cation in aliphatic alcohol, preferably absolute methanol, and mixing imidazolidinone acid or imidazolidinone acid of formula I with an alcoholic solution of cation, preferably in an inert gas stream such as nitrogen, argon or the like, at a temperature between about 15 and 35 ° θ · In this reaction, generally about one equivalent of a cationic salt formed, such as sodium, potassium, calcium or barium, in the form of hydroxide, carbonate, bicarbonate, or the like, is used to convert one equivalent of a compound of formula I as an acid into suitable salt with alkali metal or alkaline earth metal.

To obtain compounds of formula I wherein R is ammonium or organic ammonium, the acid of formula I is dissolved or dispersed in an organic solvent such as dioxane, tetrahydro furan (THE) or the like, and the mixture is treated with one equivalent of ammonia or amine or tetralkylammonium hydroxide. Of the amines that can be used in the above reaction are: methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine, isobutylamine, sec-butylamine, n-amylamine, iso-amylamine, hexylamine, heptylamine,

-17oktilamin, nonilamin, decilamin, undecilamin, dodecilarain, tridecilamin, tetradecilamin, pentadecilamin, heksadecilamin, heptadecilamin, octadecylamine, methylethylamine, metilizopropilarain, metilheksilamin, metilnonilamin, metilpentadecilamin, methyloctadecylamine, etilbutilamin, etilheptilamin, etiloktilainin, heksilheptilamin, heksiloktilamin, dimethylamine, diethylamine, di -npropylamine, diisopropylamine, di-n-amylamine, diisoamylamine, dihexylamine, diheptylamine, dioctylamine, triraethylamine, triethylamine, tri-n-propylamine, triisopropylamine, tri-n-butylamine, triisobutylamine, tri-sec-butylamine, tri-n-butylamine, tri-n-butylamine amylamine, ethanolamine, n-propanolamine, isopropanolamine, diethanolamine, N, R-diethylethanolamine, N-ethylpropanolamine, N-butylethanolamine, allylamine, n-butenyl-2-amine, n-pentenyl-2-amine, 2,3-dimethylbutenyl- 2-amine, dibutenyl-2-amine, n-hexenyl-2-amine, propylenediamine, bovine tallow amine, cyclopentylamine, cyclohexylamine, dicyclohexylamine, piperidine, morpholine, and pyrrolidine. Of the tetraalkylammonium hydroxide the following were investigated: methyl, tetraethyl, trimethylbenzylammonium hydroxides. In practice, ammonium or organic ammonium salt is precipitated and can be separated from the solution by conventional means by filtration or centrifugation, or the reaction mixture can be concentrated and the residual solvent removed with hexane, and the residue is then dried to remove ammonium or organic ammonium salts. The reactions for the conversion of the acids of formula I into the salts of formula I described above can be graphically illustrated as follows:

• GOOH

H * 1 i— N --- R, W

Base

where Rp are Rp, W, X, Y, Z and A as defined in the reference to formula I above _v ab is a cationic salt formed.

When R ^ and Rp represent different substituents, the carbon to which R ^ and Rp are attached is asymmetric carbon, and the products (as well as their intermediates) exist in the d- and 1- forms as well as the dl-form.

As indicated above, the novel herbicidally effective compounds of formula I imidazolidinone and imidazolidinone according to the present invention exhibit significant chemical and biological similarities, ensuring the integrity of the structure of the compound.

Although the final products of the present invention of Formula I are chemically and biologically similar, it is normal for the aromatic and heteroaromatic function to be altered also at the intermediates, and therefore the process for preparing them is altered. According to Thorne, syntheses for certain suitable aromatic and heteroaromatic functions will be discussed here separately for guidance and clarity later.

Esters and salts of 5-oxo imidazolinyl benzoic acid derivatives not containing one or the other or one nitro, halogen, or

Cp-C, an alkyl radical, and a carboxylic function on the aromatic ring of imidazolinyl benzoic acid in the form of an ester or salt are described in U.S. Pat. Patent 4,188,487. Protected compounds are the executable herbicidal agents, but their use requires selective crop protection against weeds.

-19 Although the present invention includes, as intermediates, certain protected oxo derivatives of 2-imidazolidinyl benzoic acids in the form of esters and salts having a carboxylic function and not containing one or the other or one substituent on the aromatic ring, the patents do not give or suggest imidazolidinyl of the present invention any method for preparing the esters or salts of the compounds of formula II 2- (2-imidazolidinyl) benzoic acids of the present invention.

According to the invention, the intermediates required for the preparation of esters and salts of 2- (2-imidazolidinyl) benzoic acids of formula II of the present invention are represented by the following structure:

X

Z wherein R, R-1, Rp, R4, W, X, Y and Z as described above can be obtained by reaction of a suitably substituted benzoic acid of formula XV with thionyl chloride and a catalytic amount of dimethylformamide (DMF). The mixture is mixed with an anhydrous aromatic solvent, such as toluene, xylene or the like, and the solution is evaporated. The residue is then diluted with an anhydrous non-protoic solvent such as tetrahydrofuran and the resulting mixture is mixed with the growth of di (C 1 -C 4) alkylamine in an anhydrous non-protoic solvent. This reaction is best carried out in an inert gas stream at a temperature between about -10 and i-10 ° C to give the compound of formula XVI, substituted N, N-diC 1 -C 4 -alkylbenzamide. This benzamide substituted formula XVI product is then treated with sec-20butyl lithium in an anhydrous non-protoic solvent such as tetrahydrofuran (TUF) in the presence of N, N, N ', Ν′-tetramethylethylenediamine (TMEDA). The reaction mixture is preferably maintained in an inert gas stream, such as nitrogen, at a temperature between about -75 and -65 ° C. Then, the reaction mixture was mixed with anhydrous carbon-saturated THF and then mixed with water. The aqueous phase is separated, cooled to between 0 and 10 ° and acidified to give the compound of formula XVII substituted phthalic acid. These reactions can be illustrated as follows:

1. K.at. DMF

2. HN (alkyl) .2 (xv)

(XVI)

Sec-BuLi

1. THF / TMEDA

2. C0 ₂

(XVII)

-22 where X, Y, Z, and R ^ are as defined in the reference to compounds of formula III, except that it cannot be fluorine.

Compounds of formula XVII substituted phthalic acid are treated with excess acetic anhydride, heated to reflux and concentrated in vacuo with an aromatic anhydrous solvent such as toluene, xylene or the like, to give substituted phthalic acid anhydride of formula XVIII. It is then dissolved in an anhydrous non-protoic solvent such as THP and treated with an equolar amount of a compound of formula XIX aaminocarbonitrile such as 2-amino-2,3 "dimethylbutyronitrile and trialkylamine such as triethylgmin or trimethylamine at a temperature between about 20 and 3θ ° θ · After that, the solvent is removed and the residue is heated to reflux in excess acetic anhydride to give substituted 1,3, dioxo-2-isoindolinalkylnitrile of formula XXI. It is understood that when X, Y, Z or R4 is hydroxyalkyl or NHR4, these groups are protected as ka acetyl derivatives prior to treatment of acids or diacids with thionyl chloride or acetic anhydride. Acetyl protecting groups are then removed after or during the formation of the imidazolinone ring.

Alternatively, a compound of formula XVIII substituted phthalic anhydride reacts with an equolar amount of a compound of formula XIX substituted α-aminocarbonitrile to heat the mixture to reflux temperature in the presence of a chlorinated hydrocarbon as a solvent, for example such as ethylene chloride, methyl dichloro, and dihydrochloride, and dihydrochloride. an isomeric mixture of the compounds of formula XXa and XXb of phthalic acid monoamide is thus obtained. The acids thus formed can then be cyclized to substituted 1,3-dioxo-2-isoindolinylalkylnitrile given by formula XXI by heating the reaction mixture to between about 20 and 100 ° C with excess anhydride of vinegar.

-23acid acids, preferably in the presence of a catalytic amount of sodium acetate or potassium acetate. Hydration of the thus formed substituted 3, 3-dioxo-2-isoindolinylalkylnitrile of formula XXI is accomplished by treating said compound of formula XXI with a strong acid such as sulfuric acid containing a small amount of water. This reaction yields a compound of formula XXII substituted 1,3-dioxo-2 isoindolinylalkylamide and is generally carried out at temperatures between about 30 and 60 ° G. After heating, the mixture is poured over ice and extracted with a chlorinated hydrocarbon such as chloroform, methylene chloride and the like. The solvent is then best removed by concentration in vacuo. the same with an equimolar amount of sodium methoxide in the presence of lower alkyl alcohol, preferably at a temperature between about 20 and 30 ° C. The reaction mixture was then neutralized to pH 7 with acetic acid to give the isomeric mixture of carbamoyl phthalic acid esters given by formulas XXIIIa and XXIIIb. The cyclization of the carbamoyl phthalic acid esters is then carried out by reacting them with an approximately 2-molar equivalent excess of phosphorus pentachloride in the presence of anhydrous toluene at a temperature between about 20 and 30 ° C. The reaction mixture was poured over ice to give the hydrochloride salt of the corresponding 2- (2-imidazolin-2-yl) benzoates of formulas XXIVa and XXIVb. Treatment of these hydrochlorides of formula XXIVa and XXIVb with one equivalent of the base cacto is alkali metal bicarbonate, the hydroxide carbonate then yields methyl benzoate of formulas XXIVa and XXIVb.

The above reactions are graphically illustrated in Scheme I following.

-24Bema I

Δ

CH ₂ C1 ₂

vinegar anhydride (ΧΧα)

(XXI)

H ₂ S0 ₄

(XXII)

-25 Scheme I (continued)

ONH2

(XXIVa)

1. PCI5

2. Base

(XXIVb)

-26 Suitable process for the preparation of substituted 5-oxo (and thioxo) -2-imidazolin-2-yl) benzoic acids of formulas XXVIIIa and XXVIIIb, which are used as intermediates for the preparation of compounds of formula II oxo and thioxo 2- (2-imidazolidinyl) benzoic acids acid, comprises the preparation of a substituted or unsubstituted phthalic anhydride of formula II by reaction of a substituted or unsubstituted phthalic acid of formula XVII with acetic anhydride, dimethoxyethane and pyridine. The phthalic acid anhydride of formula XVIII thus obtained is then mixed with an equivalent amount of a compound of formula XXVI carboxamide or thiocarboxamide, in the presence of an inert organic solvent such as a low-boiling ether (diethyl ether, tetrahydrofuran, dimethoxyethane) acetonitrile, ethyl acetate or ethyl acetonitrile, ethyl acetate or ethyl acetonitrile; 20 and 60 ° C, preferably at 25 to 55 ° θ in a stream of inert nitrogen gas. When the reaction is substantially complete, the product is isolated in the usual way, for example, by straining, distilling the solvent or extracting it into an aqueous base if the solvent does not mix with water. The reaction yields isomeric phthalamine monoacids / monoamide products, formulas XXVIIa and XXVIIb.

The mixture thus formed is then heated to about 25 to 100 [deg.] C., with about 2 to 10 molar equivalents of aqueous alcoholic sodium or potassium hydroxide. The reaction is best carried out in an inert gas stream such as azole. If the product does not dissolve in water, it is precipitated from the aqueous phase and separated by filtration or extraction. If the product is dissolved in water, the mixture can be extracted with an organic solvent such as ether, methylene chloride and the like, so the extract is concentrated and an isomeric mixture is obtained

- Substituted or unsubstituted 2- (5-oxo (or thioxo) -2-imidazolin-2-yl) benzoic acids of formula XXVIIIa and of formula XXVIIIb, respectively. With these compounds of formulas XVIIIa and XVIIIb, wherein W is sulfur, conversion to the corresponding compounds of formula II substituted or unsubstituted 2- (5-thioxo-2-imidazolidinyl) benzoic acid in the form of an isomeric mixture is carried out by reduction with NaCNBH1 as described above . It has also been found that certain compounds of formula XXVIIIa and formula XXVIIIb, wherein W is oxygen, by reduction with sodium cyanoborohydride give the corresponding compounds of 5-oxo-2- (2-imidazolidinyl) benzoic acid of formula II. However, depending on the substitution on the aromatic ring of the aforementioned compounds, some compounds of formula XXVIIIa and formula XXVIIIb have been found unsuitable or not readily available for reduction with sodium cyanoborohydride. Thus, when the compounds of formula XXVIIIa and XXVIIIb oxo derivatives are not suitable for reduction, the preparation of compounds of formula II 5-oxo derivatives of 2- (2-imidazolidinyl) benzoic acids and / or esters is carried out in an aldehyde manner. The above reactions are graphically illustrated according to Scheme II which follows:

v

-28 Scheme II

Ac ₂ O

Pyridine

DME (dimethoxyethane)

R3 (XVII) (XVIII)

^r 2 (XVIII) (XXVI)

THF

-29Sem II (continued)

(XXVI)

N —NH ₂

00H «2 * (XXVIΙα) (XXVIIb)

ΝαΟΗ, Δ

(ΧΧΥΙΙΙα) (XXVIIIb)

-30 From the above discussion, it can be seen that many synthetic pathways for 2- (2-imidazolidinyl) benzoic acids and / or esters of formula II provide mixtures of herbicidally effective acids or ester isomers. Although isomeric compositions have been found to be very effective in selectively controlling undesirable plant species, it has also been found that not infrequently, one of the isomers is more effective and / or more selective than the other. Thus, it is sometimes desirable to perform direct synthesis for a single isomer.

As an example of a sunthetic method for a single isomer of the 3-nitro phthalic anhydride of formula XXIX, it may be dispersed or dissolved in excess C 1 -C 4 alcohol and heated to reflux, generally between about 60 and 100 ° C. After refluxing, the alcohol was evaporated in vacuo and the residue was recrystallized from ethyl acetate to give the compound of formula XXX with an open ring 2-alkyl 3-nitrophthalate. The compound of formula XXX is then dispersed in thionyl chloride and the resulting mixture is maintained at a temperature between about 20 and 40 ° C until essentially the completion of the reaction. The mixture was concentrated and the residue collected in an aromatic solvent such as toluene and re-concentrated to give the compound of formula XXXI alkyl 2- (chlorocarbonyl) -6-nitrobenzoate. This compound of formula XXXI nitrobenzoate is then mixed with about an equimolar amount of substituted α-aminocarboxamide of formula XIX and heated to reflux in the presence of a non-protoic solvent such as tetrahydrofuran and trialkylamine to give carbamoyl-6-nitrophthalamate form. of the formula XXXII carbamoyl6-nitrophthalamate to the compound of formula XXXIII 2- (2-imidazolin-2yl) -6-nitrobenzoate is then carried out with phosphorus pentachloride at elevated temperature, generally between 60 and 100 ° C. The reaction is

-31 is best performed in the presence of an inert organic solvent such as toluene or benzene. The above reactions are graphically illustrated in Scheme III which follows:

Scheme III

(XXIX) (XXX)

NH _{2 ——} conh ₂ r ₂

THF

NHEt3

onh ₂ (XXXII) (XIX)

PCI 5 toluene

(XXXIII)

-32.

Another method for the preparation of mono-substituted and multi-substituted 2- (2-imidazolinyl) benzoic acids and esters, many of which are useful as intermediates for the preparation of iraidazolidinone and imidazolidinethion according to the present invention by reduction with sodium cyanoborohydrohydride , substituted benzoic acids with thionyl chloride and a catalytic amount of dimethylformamide to give the substituted benzoyl chloride of formula XXXIV. The reaction is best carried out by heating to between 25 and 40 [deg.] C. and then the reaction mixture is evaporated in vacuo with an anhydrous aromatic solvent such as toluene to give substituted benzoyl chloride, which is then mixed with equimolar amounts of the compound of formula XXVI carboxamide or thiocarboxamide and trialkylamine, such as triethylamine, triisopropylamine or the like, in the presence of a non-protoic solvent such as tetrahydrofuran.

During the addition of the reactants, the reaction mixture is generally maintained at a temperature between about 0 and 15 ° C. When the addition is complete, the mixture is allowed to warm to ambient temperature, then treated with water and extracted with an organic solvent such as ethyl acetate to give the R-substituted benzamide of formula XXXV. The substituted benzamide thus formed is then heated to a temperature of from 25 to 110 ° C with about 2 to 10 molar equivalents of aqueous alcoholic sodium or potassium hydroxide, preferably in an inert gas stream such as nitrogen. The reaction yields a compound of formula XXXVI substituted phenyl imidazolinone or imidazolintion, which is then converted to the corresponding (5-oxo (or 5-thioxo) -2-imidazolin-2-yl) benzoic acid of formula XXXVII using sec-butyl lithium and carbon dioxide. This reaction does

-33 is best effected by dissolving or dispersing a compound of formula XXXVI substituted phenyl imidazolinone or imidazolintion in tetrahydrofuran or other non-protic solvent and about three equivalents of tetramethylenediamine in a nitrogen stream. The reaction mixture is then maintained at a temperature between about -70 and -50 ° C and then treated with a solution of sec-butyl lithium in cyclohexane. Thereafter, the reaction mixture was mixed with carbon dioxide saturated tetrahydrofuran to give substituted (5-oxo (or thioxo) -2-imidazolin-2-yl) benzoic acid of formula XXXVII. These reactions are shown graphically in Scheme IV which follows:

--34-

SOC1 ₂ (xv)

M

1H-C-NH ₂ R2 (XXXV)

Sam

(XXVI)

NaOH

(XXXVI) (XXXVII)

-35Alternatively, a substituted benzoic acid of formula XV may be converted to benzoyl chloride of formula XXXIV, as described above. Subsequently, the benzoyl chloride is dispersed in THF and mixed, with a solution of 3 to 5, preferably about 4 equivalents of diethylamine in tetrahydrofuran. The addition is generally carried out under a stream of nitrogen maintaining the temperature of the reaction mixture between about -10 and 0 ° C. The reaction yields a substituted benzamide of formula XXXVII, which is then dissolved in anhydrous tetrahydrofuran and treated with an equivalent amount of sec-butyl lithium dispersed in cyclohexane. This treatment is usually carried out in a nitrogen stream, maintaining the temperature of the reaction mixture between about -70 and -50 ° C. Then, the reaction mixture is mixed with anhydrous tetrahydrofuran saturated with carbon dioxide to give substituted phthalamic acid of formula XXXIX, and its treatment by mixing the solution in dry tetrahydrofuran with ethyl chloroformate and then with triethylamine and a solution of the compound tetrahydroxide hydroxide substituted Ν, diet-diethylphthalamide of formula XL. Cyclization with a base of substituted Χ, diet-diethylphthalamide of formula XL is carried out by heating said compound of formula XL with from 2 to 10 molar equivalents of aqueous or aqueous alcoholic sodium or potassium hydroxide to a temperature of between about 25 and 110 ° C, preferably in a nitrogen stream. provides substituted N, N-diethyl (5-oxo (or thioxo) -2-imidazolin-2-yl) benzamide formula XLO which is readily converted to the corresponding acid of formula XLIII by heating with a concentrated mineral acid such as concentrated hydrochloric acid or hydrobromic acid. After acidification, the mixture was cooled, basified to pH between 7 and 10, with sodium or potassium

-36 hydroxide and then carefully acidified to pH 5 with concentrated sulfuric acid. Substituted N, N-diethyl (5-oxo (or thioxo) -2-imidazolin-2-yl) benzamide of formula XLI is also subject to transesterification with methanol and hydrogen chloride to give the corresponding methyl ester of formula XLII of said N, K-diethylaminobenzamide of formula XLI. Treatment of substituted methyl (5-oxo (or thioxo) -2-imidazolin-2-yl) benzoate of formula XLII with an aqueous or aqueous alcoholic solution of an alkali metal hydroxide at an elevated temperature between about 60 and 100 ° C, then acidification with hydrochloric acid affords substituted (5 - Oxo = Fil-1-oxo) 2-imidazolin-2-yl) benzoic acid of formula XLIII. These reactions are illustrated in Scheme IVa below. Although these reactions are illustrated graphically with respect to the substituent e for Rp R ^ ₅ X »Y,

Z and W, of course these reactions are particularly applicable to compounds in which W is oxygen, A is CR ^, R ^ is fluorine, and R,

R-ρ Rg, X, Y and Z are as described in Formulas XLI, XLI and XLII substituted (5-oxo-2-imidazolin-2-yl) benzoic acids, esters and salts.

-37 Scheme IVa

(XV) (XXXIV)

ONEt ₂

NHEt ₂

1 · SeK-BuLi 2. “ChOf

EtOCOCl / NEt ₃

H

NH ₂ ——— C — NH 2 R2 (XXVI)

-38 Scheme IVa (continued)

(XLII)

NaOH (XLI)

I.Konc. HCl

(XLIII)

-39Alternative process for the preparation of substituted 2- (5-oxo (or thioxo) -2-imidazolin-2-yl) benzoic acids, involves the reaction of a substituted benzoyl chloride of formula XXtyl carboxynide or thiocarboxamide in the presence of trialkylamine and a tetrahydrofuran solvent, which is heated to 25-110 ° C with excess aqueous or aqueous alcoholic sodium or potassium hydroxide to give the compound of formula XLIV substituted with phenyl imidazolinone or imidazolinethione. These reactions are similar to the initial reactions described above and are illustrated in Scheme IV, however, when an additional C 1 -C 4 alkyl substituent on the substituted ring of the aforementioned compound of formula XLIV ^ imidazolinone or ± imidazolinethione, said imidazolinone or imidazolintion is desired can be dissolved in anhydrous tetrahydrofuran and treated with sec-butyl lithium sulfate, best dissolved in cyclohexane or other aromatic solvent. Addition of sec-butyl lithium to imidazolinone iii.imidazolintione is best carried out over a long period, up to several hours, maintaining the reaction mixture at a temperature between about -50 and -75 ° θ · When complete, the reaction mixture is allowed to warm up to between -10 and -50 ° C and then mixed with C 1 -C 4 alkyl iodide dispersed in tetrahydrofuran. After stirring, the reaction mixture was allowed to warm to ambient temperature and then the solvent was evaporated in vacuo to give a multi-substituted product of formula XLV. The reaction is graphically given in scheme 'V., using methyl iodide and sec-butyl lithium for illustration.

When it is desired to obtain a halogen substituent on the aromatic

-40 a ring of substituted imidazolinone or imidazolinethione of formula XLIV, said substituted imidazolinone or imidazolinethion is dispersed in an anhydrous non-protoic solvent such as tetrahydrofuran and treated with sec-butyl lithium dissolved in cyclohexane. The addition is carried out over a period of about 0.5 to 2 hours maintaining the reaction mixture at a temperature below about -50 $ C. The mixture is then warmed to a temperature between about -10 and -40 [deg.] C. and cooled with a halogenating agent such as hexachloroethane or the like, preferably dispersed in an anhydrous aprotic solvent tetrahydrofuran. The mixture was then allowed to warm to ambient temperature, treated with ice-saturated salt solution and then acidified to pH J with a strong mineral acid. Thereafter, the halogenated product of formula XLVI is extracted from a reaction mixture with an organic solvent such as ether. The halogenated imidazolinone or imidazolinethione of formula XLVI is then readily converted to the corresponding substituted 2- (57px_o (or thioxo) -2-imidazolin-2-yl) benzoic acid of formula XLVII by the reaction of said halogenated imidazolinone or imidazolinithium tetramutilutamine with tetramutilutamine a stream of nitrogen, and then the resulting reaction mixture was mixed with anhydrous tetrahydrofuran, saturated with carbon dioxide. The product of formula XLVII can be isolated from the reaction mixture by dispersing said mixture in water and acidifying it with the same strong mineral acid. The organic phase is then separated from the mixture and extracted with a base. The aqueous phase was separated and acidified with mineral acid to give the desired product. These reactions are shown in Scheme V which follows:

-41Sema V

CH ₃ -

HN-R ₂ (XLIV)

(XLV) (XLVI)

-42 Scheme V (continued)

1. Sec-BuLi

2. C0 ₂

s /

-43 Another alternative process for the preparation of substituted (5-oxo (or thioxo) -2-imidazolin-2-yl) benzoic acids, esters and salts is graphically illustrated in Scheme VI below. It can be seen from this that the substituted benzoyl chloride is treated with about 3 to 5 equivalents of di-C 1 -C 4 alkylamine, such as diethylamine in tetrahydrof uranium, to give the corresponding substituted benzamide, which is then halogenated, if desired , after treatment with sefr-butyl lithium in the presence of tetrahydrofuran or other similar solvent. Sec-Butyl lithium is generally dissolved in cyclohexane and added to the benzamide contained in the reaction mixture, maintaining the temperature below -50 ° C, e.g., -50 to -75 ° 0 · When complete, the mixture is stirred. it is heated to -30 - -40 ° C and a halogenating agent such as hexachloroethane dispersed in a non-protoic solvent is added to it. This produces a halogenated substituted benzamide derivative which is easily converted to the corresponding substituted phthalamic acid by reaction with secbutyl lithium in tetrahydrofuran and tetramethylenediamine in a nitrogen stream, after which the thus obtained composition is mixed with carbon tetrahydrofuran saturated. The reaction of the thus formed product, substituted phthalamic acid, with ethyl chloroform and then with triethylamine and a solution of the carboxamide or thiocarboxamide of formula XXVI in anhydrous tetrahydrofuran yields substituted Ν, diet-diethylphthalamide, which is then subjected to boiling, or aqueous with alcoholic sodium or potassium hydroxide. The reaction provides substituted benzamide which is readily converted to the corresponding acid by treatment with a strong mineral acid or to the corresponding ester by transesterification with a G ^ -G ^ alcohol, such as

-44 Methanol and strong mineral acid, as shown in Scheme VI. The ester thus obtained can then be heated with alkali metal hydroxide and acidified with a strong mineral acid to give substituted (5-oxo- (or thioxo) -2-imidazolin2-yl) benzoic acid. These reactions are illustrated in Scheme VI (VI following), and it can be seen that the final stages of this synthetic mode are similar to the last states of preparation illustrated in Scheme JV, although the previous stages of the system differ. It should be noted that this reaction sequence results in the cropping of the isomers of the compound obtained by the prefix scheme V ^ ..

Scheme VI fr

1. Sefc-BuLi

2. CCI3-CCI3

1. Sefc-BuLi

2. C0 ₂

C1

VI (continued) (7 ''

K nh ₂ ——c— ^nh 2 R2

1. EtOCOCl / NEt ₃

2. NaOH

-47 Preparation of (5-oxo-2-imidazolidinyl) benzoic acids, esters and salts of formula II, having a 3-fluoro substituent, with or without additional substituents in the positions 4, 5 and / or 6 of the aromatic ring, may be carried out with appropriate substituted fluorine-N, N-dialkylbenzamide of formula XLVIII, such as fluorine-N, Ndiethylbenzamide. Synthesis involves the reaction of a suitably substituted fluorine-N, N-diethylbenzamide with sec-butyl lithium in a nitrogen stream, preferably in the presence of tetrahydrofuran and at a temperature between about -70 and -5θ ° θ · After that, the reaction mixture is treated with anhydrous dimethylformamide maintaining the temperature the same between about -50 and -70 ° G. After warming to ambient temperature, the mixture is treated with brine and extracted with an organic solvent such as ethyl acetate. The aqueous phase ace was separated and acidified with Jacob mineral acid to pH 3-4 to give 4fluoro-3-hydroxyphthalide of formula XLIX or substituted 4-fluoro3-bidroxyphthalide. The 4-fluoro-3-hydroxyphthalide thus obtained is then mixed with an alkali metal carbonate such as sodium or potassium carbonate and at least an equimolar amount of C 1 -C 4 alkyl iodide such as methyl iodide and a lower alkyl ketone such as acetone. Heating the resulting mixture to reflux yields 3fluoro-2-formylbenzoate of formula L or substituted 3-fluoro-2formylbenzoate.

Thus formed 3-fluoro-2-formylbenzoate or substituted

The 3-fluoro-2-formylbenzoate is then mixed with an approximately equimolar amount of a suitably substituted aminoamide of formula XII and heated in the presence of an organic acid such as N -toluenesulfonic acid and an aromatic solvent such as toluene, xylene or the like, to give 3 -fluoro- (carbamoyl) formim-48doyl benzoate of the formula LI, which is then cyclized by treatment with trifluoroacetic acid in the presence of a chlorinated hydrocarbon as a solvent, e.g., methylene chloride, dichloroethane or chloroform. The reaction is best carried out in an inert gas stream such as nitrogen by maintaining the temperature of the reaction mixture between about -5 and + 5 ° C. The reaction gives a mixture of cis- and trans-isomers 3-fluorine

4-Oxo-2-imidazolidinyl benzoate given by the formulas Lila and IIIb. .The reactions are graphically illustrated in Scheme VII which follows:

49Seraa VII

K2CO3, alkyl and acetone.

f ¹

ΝΗ ₂ - ^ - γ — C0NH ₂ R2 (XII)

-50 Scheme VII (continued)

Cis (Lila)

Trans (Lllb)

-51 As stated above, it has been found that the aldehyde route described for the rebound of 3-fluoro-4-oxo-2-imidazolidinyl benzoate, illustrated in Scheme VII above, can similarly be used to obtain substituted and unsubstituted ( ^z t - oxo ( and thioxo) -2-imidazolidinyl) nicotinate and substituted and unsubstituted (4-oxo (and thioxo) -2-imidazolidinyl) -3-quinolinecarboxylate.

Substituted 4alkyl 2-formylnicotinates used in the decolorization of 2- (2-imidazolidinyl) nicotinate of formula III, using the procedure with the aldehyde described above and illustrated in Scheme VII, for the synthesis of compounds of the formula Lila and IIIll substituted <

3-Fluoro-4-oxo-2-imidazolidinyl benzoates can be obtained from substituted θ ^ -0 ^ 2 and ^alkyl 2-methylnicotinate. Delighted and for clarity. The following synthesis is described using substituted methyl 2-methylnicotinates to illustrate this class of reactions.

In accordance with the present invention. equivalent amounts of substituted methyl 2-methylnicotinate, the formula LIH and m-chloroperbenzoic acid are mixed in the presence of a chlorinated hydrocarbon such as methylene chloride, chloroform or the like. The reaction mixture was heated to reflux, then cooled to ambient temperature and the excess per-acid was destroyed by addition of excess 1-hexene. Subsequently, the solution is washed with sodium bicarbonate solution, dried and concentrated to give the corresponding substituted methyl methyl methicotinate 1-oxide of formula LIV, which is then heated from about 70 to 95 ° θ θ ^{81 with} excess acetic anhydride to give substituted methyl 2 -acetoxymethylnicotinate of formula LV. A solvent such as pyridine or pyridine / dimethoxyethane may also be used in the reaction, but this is essentially immaterial. Oxidation of acetoxymethyl-52nicotinate of formula LV with hydrogen peroxide in acetic acid gives methyl 2-acetoxymethylnicotinab 1-oxide of formula LVI, which is readily converted to methyl 2-diacetoxymethylnicotinate of formula LVII by reaction with an excess of acetic anhydride at a temperature of about 70 ° C and about 70 ° C , ^with or without co-solvents such as pyridine or pyridine / dimethoxyethane. Treatment of methyl diacetoxymethylnicotinate of formula LVII with an alkali metal alkoxide such as sodium methoxide, sodium ethoxide, potassium butoxide,. or the like, in the presence of a C 1 -C 4 aliphatic alcohol then yields a substituted alkyl formylnicotinate such as methyl 2-formylnicotinate of formula LVIII.

Alternatively, it has also been found that the reaction of substituted ° 1 ^_ θ12 nlki · ¹ · 2-methylnicotinate of formula LIH, with benzaldehyde at elevated temperature, yields methyl 2-styrylnicotinate of formula LIX which, when exposed to ozone, gives substituted alkyl formylnicotinate of formula LVIII.

Also, it has been found that treating a substituted methyl 2acetoxymethylnicotinate of formula LV with an alkali metal alkoxide such as nate methoxide, in the presence of a lower aliphatic alcohol at elevated temperature, gives the corresponding substituted methyl 2-hydroxymethylnicotinate of the formula LX, which is further substituted by the formula III by oxidation with selenium dioxide or lead tetraacetate.

ΐ

The above reactions are graphically shown in the VITI scheme.

-53 Scheme VIII

X

'with —CHO

° 3

* h ₂ o ₂

SeO ₂ or Pb (0Ac) 4

-54Bema VIII (continued)

anhydride. acetic acid-- ·

(LVIII)

-55Reduction of quinolic acid diesters with diisobutylaluminum hydride is also an effective method for alkyl 3-formylnicotinate. The synthesis of these quinolic acid diesters is Described in European Patent Application 81105638,3 Publication Number 0 041 623.

The aldehyde pathway for the preparation of compounds of formula LVIIa and LVIIb substituted (4-oxo (and thioxo) -2-imidazolidinyl) benzoates is a similarly efficient method for the preparation of substituted and unsubstituted (4-oxo-2-imidazolidinyl) quinoline-3-carboxylates from quinoline-3-carboxylates -formylquinoline-3-carboxylate.

A process for the preparation of these substituted 2-formylquinoline3-carboxylate intermediates involves the reaction of a suitably substituted aniline, formula LXI:

wherein L, M, Ry and Rg are as defined in the reference to formula IV for 2- (2-imidazolidinyl) quinoline-5-carboxylic acids, esters and salts; with an approximately equimolar amount of the keto ester of formula LXII having the structure:

r »-CO-gh ₂ ooor '*' (LXII) where R 'is CH ^ or COOR and R is C 1 -C 4 alkyl. This reaction is optionally carried out in the presence of an organic sulfonic acid such as? -Toluenesulfonic acid in the form of hydrate, camphorsulfonic acid or aniline hydrochloride, in the presence of an organic solvent such as cyclohexane, toluene, benzene, xylene, monochlorobenzene, orthodichlorobenzene , or the like, at a temperature of about

-5620 to 110 ° C. It is best to continually remove the water formed during the reaction by distillation or at atmospheric or reduced pressure such as 6.665 RPa of mercury column pressure while maintaining the reaction temperature in the range of 75 to 80 ° C.

The reaction gives 0-anilino-a, 0-unsaturated ester of formula LXIII: L M HC-COOR Q - T ji g_R · ^(LXIII) - R ^H R? where L, M, v R _o and R 'as well as R described above.

Thus formed by β-anilino-a, the -O ~ unsaturated ester of formula LXIII is then reacted with an approximately equimolar amount of immonium salt having the structure:

© o

Cl-CH = N- (R ''') ₂ .C1 ^W (LXIV) where R'"θι" θ6 is alkyl or

Cl-CH = N (CH ₂ ) _n .Cl (LXIVa) where n is 4 or 5 and refers to formula LXIV and formula LXIVa respectively. The reaction is carried out in the presence of a hydrocarbon solvent such as toluene or a chlorinated hydrocarbon such as methylene chloride, dichloroethane, orthodichlorobenzene, chlorbenzene, or mixtures thereof, at a temperature between about 40 and 110 ° C for a time sufficient to substantially lower the reaction is complete and the alkyl ester of 2-methyl-3-quinolinecarbonyl acid of formula LXV is obtained, if R 'CH 2 is in O-anilino-a, O-unsaturated ester of formula LXVII or quinoline-2,3-dicarboxylate if R * is COOR in The 0-anilino-a, 0-unsaturated ester of formula LXVIII,

-57Alternatively, a substituted aniline of formula LXI, in which L,

M, R? and Rg are as described above, can ¹ , react with about an equi-polar amount of acetylene dicarboxylate of formula LXVI whose structure is:

ROOC-C = C-COOR, where R ^M is C 1 -C 6 alkyl. This reaction is generally carried out in the presence of a solvent such as dichloroethane or a C 1 -C 4 alcohol such as methanol at a temperature between 0 and 100 ° 0 to give a β-anilinoα, a β-unsaturated ester of formula E, which is then reacted with Immonium salts of formula LXIV having the structure of:

Cl-OH-N- (R '') 2Ci ^e where R '' is C 1 -C 6 alkyl or LXIVa whose structure is:

Cl-CH = N (CH _o ) ". 01 v? ^{2 n} where n is 4 or 5 · In the formulas LXIV or LXIVa, the anion is represented by Q as Cl, but it should be known that when POCl ^ is used to store the Vilsmeier reagent, the anion is POgC ^. This reaction is generally carried out in the presence of solvents such as methylene chloride, dichloroethane, monochlorobenzene, orthodichlorobenzene, or toluene at a temperature between 40 and 110 ° C for a sufficient time to complete the reaction to give the quinoline-2,3-dicarboxylate shown. formula LXVa whose structure is:

M where are L, M, Q, R?

Immonium salt of formula LXIV or LXIVa used in the above reactions-

COOR »

-COOR (LXVa) and R as described above,

-58 cyclization wells may refer to the Vilsmeier reagent. This reagent may be prepared from (Ν, Ν-dialkyl or N-alkyl-N-phenyl) formamide reaction with POCl ^ i 0001 _2, C1CO-COC1 or S0 _{2 of} 01 _a in a solvent or ugljovodoniku hlorovanom ugljovodoniku.

The conversion of 2-methyl-3-quinolinecarboxylate represented by formula LXV in which R 1 'CH 2 for the corresponding aldehyde of formula LXVII may be carried out in a similar manner as described above for the conversion of substituted 2-methylnicotinate of formula LIH into the corresponding 2-formylnicotinate of formula LVIII .

Conversion of quinoline-2,3-dicarboxylate represented by formulas LXV and LXVa to the corresponding aldehyde represented by formula LXVII

(LXVII) where are L, M, R? and Rg as well as R 'as defined above may be carried out by reacting quinoline-2,3-dicarboxylate of formula LXV with diisobutylaluminum hydride. The reaction is best performed in the presence of a non-protoic solvent such as tetrahydrofuran in an inert gas stream.

These reactions are graphically illustrated in Scheme IX which follows:

-59Sema IX

R'-CO-CH ₂ C00R (LXII)

R 0 ₂ C-C = C-COOR (LXVI)

Solvent

Δ

Cl — CH = N— (R) ₂ · α * (LXIV) or

Cl-CH = fQ (CH ₂ ) _n -Cl * (LXIVo)

Cl-CH = N— (R ') ₂ «Cl * (LXIV) or cich = JQ (ch ₂ ) _n -ci * (LXIVa)

-60 Scheme IX (Continued) (LXIVa)

(LXV)

(iBu ^ AlH ( _< iBu) ₂ AlH when R '= C00R

-61 As indicated above, Formulas V 2- (2-imidazolidinyl) thieno- and furo [3,2-b] pyridine-6-carboxylates, Formulas VI 2- (2-imidazolidinyl) -2,3-dihydrothieno- and furo [3,2-b] pyridine-6-carboxylates, formulas VII 2- (2-imidazolidinyl) thieno- and furo [2,3-h] pyridine-5carboxylates and formulas VIII 2- (2-imidazolidinyl) -2, 3-Hydrothienoic furo [2,3-h] pyridine-5-carboxylates can be prepared in accordance with the present invention. reduction of the corresponding (2-ylidazolin-2-yl) thieno- and furo [2,3-h] and [3,2-b] pyridine with sodium cyanoborohydride. ^- These 2- (2-imidazolin-2-yl) toeno- and furo [2,3-h] -product intermediates required for the preparation of compounds of formula V, VI, VII and VIII, 2- (2-imidazolidinyl) thieno- and furo [2,3-h] and [3,2-b] pyridines of the present invention are described in the application for US Letters Patent of Marinus Los, David William Ladner and Barrington Gross, serial No. 500,219, filed June 2, 1983 "s ° d · and is entered here as a reference.

2- (2-imidazolin-2-yl) thieno and furo [2,3-b] and [3,2-b] pyridine intermediates, useful for the preparation of compounds of formulas V, VI, VII, and VIII 2- (2- imidazolidinyl) thieno- and furo [2,3-b] and [3,2-b] pyridines of the present invention are given by formulas Va, Via, Vila, I Vlila:

R ^ .B

(Va) ^R ii ^- r ' ^Bx fi ^X5 V ^00R R ^{(VIa) R} 1? JN ^, / ⁱⁱ S “ ^R 2

An_i = w

in the reference to compounds of formulas V, VI, VII and VIII.

-62 It should be noted that the imidazolinone and imidazolintion imidazolinyl intermediates, which have been discussed, have been preordained by one structure, but it should be noted that the imidazolinyl function in these compounds can exist in any tautomeric form:

The intermediates of formula Va, Via, Vila and Vila for the compounds of the present invention can be obtained from the corresponding suitably substituted thieno and furo [2,3-b] and [3,2-b] pyridinecarboxylic acids and esters of formulas LXXI and LXXIa illustrated below.

Since R 1 and R 4 represent substituents selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl and phenyl radical, and R ₄ and R ₁₂ represent hydrogen, C 1-6 alkyl and phenyl: for the purposes of the following discussion, which pertains to obtain compounds of formula Va, Via, Vila and Vila, 2- (2-imidazolin-2-yl) thieno and furo [2,3-b] and [3,2-b] pyridine. the structures of the compounds covered in the synthesis and discussion will be illustrated with R ^ and R ^ q.

(ΧΧΙΧΧΙ) i

^ j-CO ^ R • _N > co ₂ r (LXXIa) where R ^, R ^ _q and B are as previously described and R is methyl or ethyl.

Methods suitable for the preparation of compounds of formula Va, Via, Vila and Vlila unsaturated compounds in which the double bond from the compounds of formula (LXXI) and (LXXIa) of pyridindicarbosilic acids in the form of esters are illustrated in scheme X below.

Thus the compounds of formula (LXXI) and (LXXIa) as diesters can be

-63hydrolyze to the corresponding thieno- and furo-2,3-pyridicarboxylic acids of formula (ΙΧΧΙΙ) and (LXXIIa) by reaction of the same with a strong base such as potassium hydroxide or sodium hydroxide. The acid anhydrides of formula (ΙΧΧΙΙΙ) and (IXXIIIa) are then prepared by treating the compounds of formula (ΙΧΧΙΙ) and (LXXIIa) of pyridindicarboxylic acids with; for example, acetic anhydride. Reaction of compounds of formula (LXXIII) and (LXXIIIa) anhydrides with suitably substituted aminocarboxamide or aminothiocarboxamide of formula (IX) yield carbamoyl nicotinic acids of formula (LXXIV) and (LXXIVa). Treatment of the compounds of formula (IXXIV) and (LXXIVa) of carbamoyl nicotinic acid thus obtained with about 2 to 10 molar equivalents of aqueous or aqueous alcoholic sodium or potassium hydroxide, preferably in an inert gas stream such as nitrogen, by cooling and acidifying to pH 2 to 4 s a strong mineral acid such as hydrochloric acid or sulfuric acid gives herbicidally effective 6- (4,4-disubstituted-5-oxo- (or thiono) -2-imidazolin2-yl) thieno- and furo [2,3-b] pyridine -5-carboxylic acids, and 5- (4,4-disubstituted-5-oxo- (or thiono) -2-imidazolin-2-yl) thieno- and furo "[3,2-b] pyridine-6-carboxylic acids · covered by formulas (Va) and (Vila).

Formula (Va) and (Vila) 5- (2-imidazolin-2-yl) thieno- and furopridine esters, in which R represents a substituent different from hydrogen or a salt-forming cation, and Rp is R4, R4, R ^ _Q and B as described above can be obtained by reacting the new thienoyl furoimidazopyrrolopyridinedione represented by formulas (LXXV) and (lXXVa) hereinafter in Scheme (XI) with a suitable alcohol and an appropriate alkali metal alkoxide at a moving temperature

-64— between about 20 and about 50 ° 0.

Compounds of formula (LXXV) and (LXXVa) thieno- and furoimidazopyroropyridinediones can be conveniently obtained from compounds of formula (Vila) and (Va) which are acids, where B is H by treatment with one equivalent of dicyclohexylcarbodiimide in an inert growth chew such as methylene chloride as illustrated in Scheme (XI) which follows:

v

-65Schema X

Λ - ^ - COOR ”N ^β ισ

COOR (LXXI) (LXXIa)

1. Aqueous alcoholic solution of NaOH

Δ

2. HCI

COOH

N (LXXIIa)

Ria

Ac ₂ 0

(LXXIIIa) —66—

Scheme X (continued) (ΙΧΧΙΙΙ) (ΙΧΧΙΙΙα) | l nh ₂ —cw-nh ₂ ^r 2 (IX) ^R 1 (T

R _r θ Λ _N ^ —CONH— (j) —CW — NH2 ^r 2

R _r ^R i <r ^{z B} V ^^ V-cooh

II _n <2 — CONH— <p-CW — NH 2 ^R Z (LXXIV) (LXXIVa)

At OH

(Villa)

DCC

(Va)

«1 (LXXV)

R30'Mi ^{+ R} 10

Rr

COOR3

N B N ·

N-

^B Υ ^Ζ ^ Ί — COOR, N—

NN? 1 - R ₂ - = W (Villa) where alkali is metal and X, I, is finalized, and is C 1 -C 4 alkyl.

(Va)

Z, Rp R ₂ are as above de

-68Many compounds of formula (LXXI) thieno [2-5-b) pyridindicarboxylic acid and formula (LXXIa) thieno [5 »2-b] pyridindicarboxylic acids can be conveniently prepared by the reaction of a suitably substituted 2 or 5-aminothiophene of formula (LXXXIV) or (LXXXIV) with the acetylenedicarboxylic acid C 1 -C 4 alkyl ester of formula (IX) as described by Bleckert et al. Chem. Ber. 1978, 106, 368. Thus formed B-aminotieno-a, B-unsaturated ester of formula (LXXXV) or (LXXXVa) © Θ then reacts with the immonium salt of formula C1-CH »N- (R” ') pCl where

Φ ©

R "'O ₁ -C ₆ alkyl or Cl-CH" NO (CH ₂ ) _n , Cl where n' is 4 or 5, in the presence of a low boiling chlorinated hydrocarbon as solvent and such as methylene chloride or dichloroethane at a temperature of about 40 and 9θ ° 0 »for a time sufficient to substantially complete the reaction to give the compound of formula (LXXI) [2, $ - b] thieno- or (LXXIa) [3» 2-b] thieno-2,3 -pyridindicarboxylic acid as dialkyl ester as illustrated in Scheme (XII) below.

Compounds of formula (LXXIa) furo [3,2-b) pyridinedicarboxylic acid are prepared by reaction of 3-amino-2-formylfuran of formula (LXXVI) obtained by the method of S. Gronovitz et al., Acta Chemica Scand B29 (1975) with ethyl oxalacetate , thus obtaining the compounds of formula (LXXIa) furopyridine compounds directly, as shown in scheme (XIII) below, while the compounds of formula (LXXIa) furo [2,3-b] pyridine compounds in which R 1 and R 2 q are H is obtained by bromination of the reaction product (LXXVII) of acetoacetamide with the diethyl ester of ethoxymethyleneoxalacetic acid and then treated with sodium borohydride and para-toluenesulfonic acid in refluxing xylene as illustrated in Scheme (XIV) below.

-69Schema XII

or ^R 10

R ₉ : NH ₂ (LXXXIV) (LXXXIVo)

R 0 ₂ C — C = C — COOR (IX) ^R 10 “r ₉ -

: i | - | ^R 1O M L-N-C-COOR or R ₉ J  1 k /

HC — COOR

H

-N-C — COOR

II

HC — COOR '(LXXXVa) (LXXXVa)

C1-CH = N— (R ') 2 .Cl®. or

Cl-CH = fQcH2) n '-Cl ^R 10 ^R ₉ / ¼-COOR

I

Λ -COOR SN or ^r 9 ^R 1O ' ^S V ^Z \ —COOR il

COOR (LXXI) (LXXIa)

-70Schema XIII

(LXXVI)

C2H ₅ 0 ₂ C- <jj-CH2- € 02C2H ₅ ”0 ° / Υ“ Λ «5 ^R 1O - * -— k _N ^ —C0 ₂ c ₂ h ₅ (LXXIa)

-71Schema XIV

OO? 02 ^c 2 ^H 5

CH ₃ —C — CH ₂ —C — ΝΗ ₂ + C2H ₅ Q- <jS = C-CO-CO ₂ C ₂ H ₅ C2 ^H 50H / NoOAc_ ·

H

48tHBr / Br ₂

NqBH4

(C2 ^h 5> 3N

OH

C0 ₂ C ₂ H ₅

I \ Z \ —CO2C2H5

O N £ -toluenes-lf-octic acid

\ z \

O N

O2C2H5 θ2 ^ 2 ^ 5 (LXXI)

Compounds with the substituents represented by R ^ and R- ^ θ in the formulas Va, Vila, LXXV and LXXVa of the present invention can be retrieved either by use of a suitably substituted starting material to obtain compounds of formulas LXXI and LXXIa thieno- and furopyridine-5,6- dicarboxylic acids in the form of esters or by electrophilic substitution (halogenation, nitration / sulfonation, etc.) directly to the compound of formula LXXI or LXXIa in the form of diesters or to the final products of formula Va or Vila, where at least one of Y or Z is hydrogen, These substituted compounds of formula (LXXI, LXXIa, Va, and Vila) can then be used as starting materials for additional Rg and R4 substitution by displacement, reduction, oxidation, and the like. Representative substituted (LXXI) and (LXXIa) compounds obtained by these methods are illustrated below.

B Δ ^R 10 R & H H ch ₅ S H Nr ch ₅ S ch ₅ H ch ₅ S H 01 • oh ₃ o 01 01 ch ₅ S H J oh ₃ S II no ₂ OH, S Nr Nr Ofi,

B Rg RlO R S ch ₃ Cl ch ₃ S H ch ₃ ch ₃ S Cl H ch ₃ S ch ₃ ch ₃ ch ₃ s H CN ch ₃ s H och ₃ ch ₃ s H N (CH ₃ ) ₂ ch ₃ s H sch ₃ ch ₃ s H ocf ₂ h ch ₃ 0 H H c ₂ h ₅ 0 H Nr ch ₃ 0 H Cl ch ₃ 0 ch ₃ H ch ₃ 0 ch ₃ H c ₂ h ₅ 0 H ch ₃ ch ₃ 0 c ₂ h ₅ H ch ₃ 0 H c ₂ h ₅ ch ₃ 0 ch ₃ ch ₃ ch ₃ s - (ch ₂ ) ₃ < ch ₃ s - (ch ₂ ) ₄ ch ₃ s ch ₃ s c ₆ h ₅ H ch ₃ 0 ^c 6 ^h 5 H ch ₃ s H · " ch ₃ ch ₃ s H oc ₆ h ₅ ch ₃ 0 H oc ₆ h ₅ ch ₃ 0 cf ₃ H ch ₃

-74 Also new herbicidal 2,3-dihydrothieno [2,3-b] and [3,2-b] pyridine compounds can be obtained in the starting sequence of Scheme XII above with dihydrothiophenein hydrochloride. New herbicidal compounds of 2,3-dihydro furo [2,3-b] and [3,2-b] pyridines can be obtained by catalytic reduction of compounds of formula Va and Vila (2-imidazolin-2yl) products, or of formula LXXI and LXXIa furo [2,3-b] and [3,2-b] pyridine-5,6-diesters such as with hydrogen and palladium on charcoal, ensuring that Rg and R _{1Q substituents} are not reduced by this process. Thus, new 2,3-dihydro herbicide compounds are provided below.

where Rq, R, _n , B, W, R ,, R _o and as described for Va and Vila. The imidazolidinone and imidazolidinone compounds of formula I of the present invention are highly effective herbicidal agents before and after emergence. useful for combating a large number of different undesirable monocotyledonous and dicotyledonous plant species. Unexpectedly, it has also been found that these compounds imidazolidinone and imidazolidinone compounds of formula I are very well tolerated by various crops including: sunflower; grass crops such as corn, rice, barley and wheat; leguminous crops such as soybean, Although the herbicidal selectivity of the compounds of formula I imidazolidinone and imidazolidinone according to the present invention vary with the structure of the compounds from crop to crop, the presence of dihydroimidazolinyl function, which is unique to all the compounds of formula I imidazolidine

The -75i imidazolidintion according to the present invention makes the compounds of the present invention very good agents with herbicidal selectivity. This selectivity allows the application of the active compounds to almost planted fields or to almost ripe crops to suppress unwanted grasses and broadleaf weeds in addition to said crops.

(It has also been unexpectedly found that the compounds of the present invention often show activity in regulating plant growth when used in non-herbicidal amounts. When applied to cereals such as wheat and barley, it is noticeable that the treated plants are shorter, less sensitive to adverse weather conditions exhibit increased shoot outbreaks and often yield higher yields than untreated crops. It has also been found to increase yields of maize and soybeans treated with the compounds of formula I imidazolidinone or imidazolidinone, the compounds of the present invention. is also the case when treating sunflower.

In practice, the compounds of formula I imidazolidinones and imidazolidine thiones can be applied to the leaves of unwanted monocotyledonous or [dicotyledonous plants, or to seed planted soil or to other plant development organs, such as tubers, rhizomes or stolons, in an amount generally between about 0.032 and 4.0 kg / ha, preferably between 0.063 and 2.0 kg / ha, although larger quantities of 8.0 kg / ha can be used if desired

Effective regulatory activity of plant growth is generally. obtained when the aforementioned compounds of formula I are applied to j crops in quantities below herbicidal amounts. Of course the amount varies from compound to compound.

-76 Compounds of formula I imidazolidinones and imidazolidinones of the present invention can be applied to the leaves of plants or to a seed-planted land or to other organs for their development, in the form of a liquid spray, as a ULV concentrate or as a solid formulation.

When strains of the compounds of formula T are obtained as alkali metal salts or organoammonium salts, said salts are often dissolved in water and can be easily dispersed in water, with or without the addition of a surfactant, and applied as an aqueous spray. Said compounds of formula I may also be obtained as wettable powders, liquid concentrates, emulsifiable concentrates, granular formulations or the like.

A typical emulsion concentrate can be obtained by dissolving about 5 to 25% by weight of the active ingredient in about 65 to 90% by weight of N, methylpyrrolidone, isophorone, butyl cellulose, methyl acetate or similar additives and dispersing therein about 5 to 10% by weight of non-ionic a surfactant such as alkylphenoxy polyethoxy alcohol. This concentrate is dispersed in water for use as a liquid spray or can be applied directly as ULV. concentrate in the form of discrete droplets whose mean mass is between about 17 and 150 microns in particle size.

The wettable powders are prepared by grinding together about 20 to 45% by weight of a finely divided carrier such as kaolin, bentonite, diatomaceous earth, atapulgite, or the like, 45 to 80 # by weight v

of the active compound, 2 to 5% by weight of the dispersant such as sodium lignosulfonate, and 2 to 5% by weight of the non-ionic surfactant, 1 such as octylphenoxy polyethoxy ethanol, nonylphenoxy polyethoxy ethanol or the like.

-77Typical flowable liquid is prepared by mixing about 40% by weight of the active ingredient with about 2% by weight of a gelling agent such as bentonite, 3% by weight of a dispersing agent such as sodium lignosulfonate, 1% by weight of polyethylene glycol and 54% by weight of water.

When the compounds of the present invention are used as herbicides when including soil treatment, the compounds can be prepared and administered as granular products. Preparation of the granular product is accomplished by dissolving the active compound in a solvent such as methylene chloride, N-methylpyrrolidone or the like. and by spraying the solution thus obtained onto a granular support such as corncobs, sand, atapulgite, kaolin and the like.

The granular product thus prepared generally contains about 3 to 20% by weight of the active ingredient and about 97 to 80% by weight of the granular carrier.

To facilitate further understanding of the invention, the following examples are provided for the purpose of illustrating certain more specific details. In this way, the invention cannot be considered to be restricted except for the defined claims. Unless otherwise noted, all parts are by weight.

'}

-78Example 1

Preparation of 3-chloro-N, N-diethyl-N-toluamide

CH

C

00H

1. Kat. DMP

2. HMEt ₂

ONEt

To a mixture of 32.2 g (0.19 mol) of 3-chloro-4-methylbenzoic acid in 100 ml of thionyl chloride was added 2 drops of dimethylformamide and heated in a steam bath for 1 hour. The clear solution of the color of the amber is evaporated in vacuo with several batches of anhydrous toluene / so the residue is obtained as an oil of the color of the amber. After dilution with a volume of 125 m and anhydrous tetrahydrofuran, 3-chloro-4-methyl-benzoyl chloride was added dropwise to a solution miscible with 43.3 ml 0 ^ 418 mol) of diebilamine · (HNEt ₂ ) in 300 ml of anhydrous tetrahydrofuran in at N ₂ at -5 ° C. The reaction mixture was allowed to stand at room temperature for 72 h and then treated with 300 ml of water. Care is taken apart; the aqueous phase is extracted with a total of 300 ml of ethyl acetate. All organic phases were combined, washed with 300 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to give 40.0 g of a clear dark red oil. The infrared and proton nmr spectra correspond to the desired structure. Gas-liquid chromatography gave a purity of 96%.

Example 2

Preparation of 3-chloro-4-methylphthalic acid

A stirring solution of 16.6 ml (0.11 mol) of N, N, N ', N'-tetramethylethylenediamine (TMEDA) in 300 ml of anhydrous tetrahydrofuran is treated dropwise with 100 ml of a 1.1 M solution of sec-butyl lithium (0 , 11 mol) in cyclohexane at -70 to -68 ° C under a nitrogen atmosphere.

-79ONEt ₂ , + SeK-BuLi

CH ₃ - <x /

Cl

1. THF / TMEDA

2. C0 ₂

After stirring at -68 ° C for 15 min, the reaction solution was treated dropwise with a solution of 22.6 g (0.10 mol) of 3-chloro-N, Ndiethyl-β-toluamide in 50 ml of anhydrous tetrahydrofuran at -65 to 60 ° C. The reaction mixture was stirred at -65 ° C for 30 min, then poured over 350 ml of anhydrous THE saturated with carbon dioxide and allowed to stir at ambient temperature for 4 days, the reaction mixture was treated with 300 ml of water, the phases were separated , and the aqueous phase is washed with a total volume of 300 ml of ethyl acetate. The aqueous phase is cooled to 5 ° 0 and carefully acidified with concentrated sulfuric acid to pell 3. The resulting oil is extracted into a total of 900 ml of ethyl acetate. The organic phases were washed with 300 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated to give an oil as an orange residue (25.1 g) which crystallized after prolonged standing. The infrared (IR) and mass spectra are consistent with the desired structure.

-80Example 5

Preparation of 5-chloro-4-methylphthalic anhydride

A solution stirring from 21.5 6 (0.10 mol) of 3-chloro-4-methylphthalic acid in 500 ml of acetic anhydride was heated to reflux for 6 h, allowed to cool to room temperature and concentrated in vacuo several times with anhydrous toluene. A viscous, dense, amber-colored syrup is obtained, analyzed by IR spectroscopy and used without further purification.

Example 4: Preparation of 4-chloro-α-isopropyl-q, 5-dimethyl-1,5-dioxo-2-isoindoline acetonitrile

N £ tq_ (CH ₃ CO) ₂ O

-81 A solution miscible with 19.7 β (0.10 mol) of 3-chloro-4-methylphthalic anhydride in 200 ml of anhydrous tetrahydrofuran is treated once with a mixture of 12.3 g (0.11 mol) of 2 amino-2,3. -dimethylbutyronitrile, 13.9 ml (0.10 mol) of triethylamine (NEt ^) and I50 ml of anhydrous tetrahydrofuran at room temperature. After 72 h, the solvent was removed in vacuo to give a quenched oil as a residue. This oil was dispersed in 200 ml of acetic anhydride and heated to reflux for 2 h, allowed to cool to room temperature for 48 h and concentrated in vacuo. so heavy black oil is obtained. After chromatography on silica gel using methylene chloride twice and a mixture of methylene chloride in hexane, 14.6 g of a light yellow solid are obtained, m.p. 104-108 ° C. This solid, 4-chloro-α-isopropyl, 5 il dimethyl-1,3-dioxo-2-isoindolinacetonitrile is analytically pure, and the IR and proton nmr spectra are appropriate with the desired structure.

Example 5

Preparation of 4-chloro-α-isopropyl-q, 5-dimethyl-1,5-dioxo-2-isoindoline acetamide

Cl 0

Cl o

CH (CH ₃ )

CH (CH ₃ ) 2

<fH ₃ conh ₂

CH (CH ₃ ) 2

Cl o

-82 A solution of 9.5 g (0.035 mol) of 4-chloro-α-isopropyl-2,5-dimethyl, 3-dioxo-2-isoindolinacetonitrile in 30 ml of methylene chloride is added dropwise to a mixture of 15 ml of 95% sulfuric acid plus 2 ml. water at 5 ° 0 · With vigorous stirring, continue for a total of 24 h at ambient temperature. ' The reaction mixture was heated to 40 ° C for 3 h and then poured over 250 ml of ice. The cold aqueous mixture was extracted with a total of 350 ml of chloroform. The organic phases were combined, washed with 200 ml of water, dried over magnesium sulfate and concentrated in. vacuum, yielding 8.8 g of a light beige solid color, m.p. 198-2O3 ° C. This solid was recrystallized from ethyl acetate / ether to give analytically Pure 4-chloro-α-isopropyl-oc, 5-dimethyl-1,3-dioxo2-isoindolinacetamide as a white solid, m.p. Mp 215-218 ° C.

The IR and proton nme spectrum correspond to the desired structure

Example 6

Preparation of 3-Chloro-4-methyl-1 - (1-carbamoyl-1,2-dimethylpropyl-phthalamic acid methyl ester

A solution stirring from 6.0 g (0.019 mol) of 4-chloro-2-isopropyl-2,5-dimethyl-1,3-diodo-2-isoindolinacetamide in 200 ml of methanol was treated in batches with 0.93 g ( 0.019 mol) 50% dispersion

-83Sodium hydride in mineral oil. After 16 h at ambient temperature, 1.1 ml (0.021 mol) of acetic acid (final pH = 7) were added dropwise and the solvents were removed in vacuo. The residue was dispersed in 75 ml of water and extracted with a total of 300 ml of ethyl acetate. The organic phases are combined, dried over magnesium sulfate and evaporated in vacuo to give a light orange-colored gum. After trituration with 50 ml of ether and filtration, 4.0 g of a light orange solid was obtained. The IR and proton nmr spectra correspond to the desired structure. This solid is used without further purification.

Example 7

Preparation of methyl 3-chloro-2- (4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl) -N-toluate hydrochloride

ONH- (j: -CONH2

CH (CH ₃ ) ₂

COOCH3

PCI 5

CH ₃

A mixture miscible with δζΐ g (0.029 mol) of phosphorus pentachloride in 100 ml of anhydrous toluene was treated in batches with 4.0 g (0.012 mol) of methyl 3-chloro-4-methyl-N- (1-carbamoyl-1, 2 -dimethylpropyl) phthalamate. After 72 h at room temperature, the reaction

-84 mixtures are poured over 350 ml of ice and stirred at ambient temperature until the ice has melted. The resulting three-phase mixture was filtered, the colorless solid was dried in vacuo at 53 ° C for 2 h to give 3.5 S methyl 3-chloro-2- (4-isopropyl-4-methyl-5-oxo-2- imidazolin-2-yl) -N-toluate hydrochloride, mp 233-235 °.

Example 8

Preparation of methyl 3-chloro-2- (4-isopropyl-4-methyl-5 ~ ^'0 ^ ⁰ ~ 2-imidazolin-2-yl) -j> -toluata

To a dispersion of 1.8 g (5.0 mmol) of the hydrochloride obtained in Example 7 in 20 ml of water was added 2.5 ml of a 2M solution of sodium hydroxide (5.0 mmol) and 50 ml of ethyl acetate. With vigorous stirring, the mixture was carefully acidified to pellet 3 with concentrated sulfuric acid. Care is taken and the aqueous phase is extracted with 50 ml of ethyl acetate. All organic phases are combined, dried over mags?

of hydrogen sulphate and concentrated in vacuo to give 1.4 g of a white crystalline residue, m.p. 178-18 ° C. A sample recrystallized from ethyl acetate gave analytically Pure 3-chloro-2- (4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl) -1 H -toluate, m.p. 181-183 ° 0.

Priroer 9

Preparation of 2-m ^ til 3-uitrophthalate

A solution containing 10 g of 3-nitrophthalic anhydride in 125 ml of absolute ethanol was heated to reflux for 16 h. Concentration of the solution gave a greyish solid residue which was recrystallized from ethyl acetate to give 2-methyl 3-nitrophthalate, m.p. Mp 154-156 ° C.

Example 10

Methyl N- (1-carbamoyl-1,2-dimethylpropyl) -6-nitrophthalamate

A suspension of 4.94 g of 2-methyl 3-nitrophthalate in 20 ml of thionyl chloride was stirred at room temperature for 72 h. The mixture was concentrated and the residue was dissolved in toluene and concentrated again. This process is repeated.

The residue '(crude acid chloride) in 30 acres of dry THP was added dropwise at room temperature while stirring in a stretch of nitrogen a solution containing 3.84 g of 2-amino-2,3-dimethylbutyramide and 4.4 ml of triethylamine in 50 ml of dry THP . After stirring at room temperature for 24 h, 50 ml of water and 50 acre were added, the phases separated and the aqueous phase re-extracted with 50 ml of ethyl acetate. The combined organic extract was dried and concentrated. The residue was triturated with ether to give the product which was recrystallized from ethyl acetate to give the desired product with m.p. 100-107 ° C.

-86The procedure of Example 10 is as follows:

1. SOC1 ₂ ? ³ nh ₂ - <j: —conh ₂ ch (ch ₃ ) ₂

^ooch 3 <pH ₃ ONH <p —— CONH ₂ CH (CH ₃ ) ₂

Example 11

Preparation of methyl 2- (4-isopropyl-4-methyl-5-oxo-2-imidazolin2-yl) -6-nitrobenzoate

00CH ₃ <^ h ₃ ONH —— C0NH ₂ CH (CH ₃ ) ₂

PCI5

A mixture containing 3.4 g of amide and 5.2 g of PCl ^ in 100 ml of dry toluene was heated in a steam bath lh. The mixture was cooled to 5 ° C and filtered to give 2.6 g of the hydrochloride salt of the desired imidazolinone, m.p. 194-197 ° C · This salt was dispersed in a mixture of 20 ml of water containing 1.0 g of sodium bicarbonate and 75 ml of ethyl acetate, and the mixture was stirred at room temperature for 16 h. The organic phase was separated, dried and concentrated to give analytically pure methyl 2- (4-isopropyl ~ 4-methyl

5-Oxo-2-imidazolin-2-yl) -6-nitrobenzoate, m.p. Mp 159-162 ° C.

Example 12

Preparation of 6-fluoro-N, N-diisopropyl-5-methylphthalamic acid

A solution stirring from 7.0 ml (0.046 mol) of Ν, Ν, Ν ', N'-tetramethylethylenediamine in 75 ml of THF under nitrogen atmosphere is treated

-87Baking with 42 ml of 1.1 m sec-BuLi solution in cyclohexane (0.046 mol) at -75 to -65 ° C. After the addition is complete, the growth-

vor 10.0 g (0.042 mol) of 3-fluoro-N, N-diisopropyl-N-toluamide in 125 ml of dry THF was added dropwise at -65 to -6Q ° C. When the addition is complete, the reaction mixture is poured over 300 ml of THF for saturated with C0 ₂ and allowed to warm to room temperature. 125 ml of ice water was added (carefully to form a foam) and the mixture was carefully acidified to pH 2-3 with concentrated sulfuric acid. The organic phases are washed with 100 ml of saturated NaCl solution, the aqueous phases are combined and extracted with a total of 300 ml of ethyl acetate. The organic phases were combined, dried over KgSO 4 and concentrated in vacuo to give 13.0 g of the residue as a glass of yellow color, which crystallized in 200 ml of ether to give 8.2 g of 6-fluoroN, I'-diisopropyl- 5-methylphthalamic acid, which is a white solid and analytically pure, mp 147 ~ 149 ° C.

Example 13

Deactivation of N ^ - (1-carbamoyl-1,2-dimethylpropyl) -3-fluoro-N ', N * -disopropyl-4-methylphthalamide

A solution stirring from 8.13 g of 6-fluoro-H, N-diisopropyl5-methylphthalamic acid in 100 ml of dry THF at -2 ° C and in a stream of nitrogen was added dropwise 2.78 ml of ethyl chloroformate and then

-884.5 ml of triethylamine. After half an hour, it is added dropwise by growth.

<f » ³

NH _{2 ——} CONH ₂ CH (CH ₃ ) ₂

C1COOC ₂ H ₅

Et ₃ N

CH ₃ · (^ \ - C0N (iPr) ₂ ? ³

CONH— (ji — C0NH ₂

X

CH (CH ₃ ) ₂ vor 3 77 g of 2-amino-2,3-dimethylbutyramide in 125 ml of dry THP at -2 to + 2 ° C. After the addition was complete, the mixture was allowed to stand at room temperature and stirred for 3 h. Add 100 ml of water to the mixture. The organic phase was separated, washed with brine, and the combined aqueous phases extracted with 100 ml of ethyl acetate. The combined organic phases were dried (MgSO4) and concentrated to give a foam that was used directly in the next phase.

Example 14

Preparation of 5-fluoro-N, N-diisopropyl-2- (4-isopropyl-4-methyl-5 'oxo-2-imidazolin-2-yl) - N -toluamide

CH ₃ | ^{/ <7} \ -CON (iPr) ₂

CONH— (p — CONH ₂ CH (CH ₃ ) ₂

X

NoOH

Dioxane

H ₂ 0 ch ₃ ·

F

HN

-89The crude product of Example 13 was dissolved in 75 ml of a 1.93 M NaOH solution, 25 ml of dioxane was added and the mixture was heated to 80 ° C for 16 h. After cooling, the mixture was acidified to concentrated to pH 3 and extracted several times with ethyl acetate. The extract was washed with brine, dried and concentrated to give a foam which crystallized from ether to give the product, 3-fluoroN, N-diisopropyl-2- (4-isopropyl-4-methyl-5-oxo-2 -imidazolin-2-yl) N-toluamide as a white crystalline solid, m.p. 205-210 ° C which is analytically pure.

Example 15

Preparation of 5-fluoro-2- (4-isopropyl-4-methyl-5-oxo-2-imidazolin2-yl) -1 H -toluenoic acid

A solution of 1.0 g (2.7 mmol) of 3-fluoro-N, N-diisopropyl-2- (4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl) - N -toluamide in 20 ml of concentrated hydrochloric acid is heated to reflux (copious solid color precipitate). Another 15 ml of concentrated hydrochloric acid was added and the solution was heated to reflux for 7 h. After cooling to room temperature, the mixture was basified to pH 7 to 10 with 6 M NaoH solution, then carefully adjusted to pH 3 with concentrated sulfuric acid. The mixture was filtered, the clear filtrate was treated with 250 ml of ethyl acetate and vigorously fried 24 b. The organic phase was separated, dried over MgSO 4 and concentrated in vacuo to give 0.44 g of a white foam crystallized from ether to give 3-fluoro-2- (4-isopropyl-4-methyl-5-oxo -2-imidazolin-2-yl) - N-oluenoic acid as a white solid, m.p. 164-170 ° G.

Example 16

Preparation of N- (1-carbamoyl-1,2-dimethylpropyl) - N -toluamide

CH ₃ _A

0C1 and ” ³

H ₂ N— <p — conh ₂ ch (ch ₃ ) ₂

NEt ₃ / THF

<j * 3

ONH-Cj: -conh ₂ CH (CH ₃ ) ₂ and contains 13.0 g (0.10 mol) of 2-amino15.3 ml (0.11 mol) of triethylamine (NEt ₇ )

CH _{3 The} mixture that mixes 2,3-dimethylbutyramide and in 150 ml of dry THF is treated dropwise at 5 to 10 ° C with a solution of 15.5 g '(0.10 mol) N -toluyl chloride in 25 ml of dry THF. P _{on the} WTO was allowed to zauzmo the temperature surroundings and standing for 16 h, the reaction mixture is quenched with 50 ml of water and stirred for 1 h. The resulting three-phase mixture is filtered; The filtrate was separated and the aqueous phase extracted with I50 ml of ethyl acetate. All organic phases are combined, washed v

with 100 ml of a saturated solution, NaCl, were dried over MgSO4 and concentrated in vacuo. 17.3 g of a white solid are obtained, t * t, 145152 ° C. The NMR spectrum corresponds to the desired structure.

Example J7

Preparation of 4-isopopyl-4-methyl-2-p-bolyl-2-ynidazolin-5-one

-91C * ₃ ->

<f » ³

ONH-C-CONH2 CH (CH ₃ ) ₂

NaOH

A mixture of 24.8 g (0.10 mol) of N- (1-carbamoyl-1,2-dimethylpropyl) N-toluamide in 263 ml of 2 H sodium hydroxide solution (0.50 mol NaOH) was heated with 100 ml of N-dioxane and heated on the steam bath for 72 h. The ^ -dioxane was removed in vacuo and the residual aqueous solution was cooled to 5-10 ° C. After being carefully acidified to pH 3-4 with concentrated sulfuric acid, the reaction mixture was extracted with a total of 750 ml of methylene chloride. The organic phase was washed with 200 ml of saturated NaCl solution, dried over KgSO 4 and evaporated to dryness in vacuo to give a solid yellow residue, weighing

22,1 g. The NMR spectrum corresponds to the desired structure. This compound was recrystallized from acetonitrile to give analytically pure 4-isopropyl-4-methyl-2 H -tolyl-2-imidazolin-5-one, m.p. Mp 151-154 ° C.

Example 18

Preparation of 2- (2-chloro-N-tolyl) * 4-isopropyl-4-methyl-2-imidazolin5-one

A mechanically stirred solution of a stirrer containing 20.0 g (0.087 mol) of 4-isopropyl-4-methyl-2-p-tolyl-2-imidazolin-5-one in 200 ml of dry tetrahydrofuran is treated dropwise with 160 ml.

-921.2 M solution of sec-butyl lithium over a period of. 40 minutes at -72 to -65 (0.191 mol) in cyclohexane ° C. After mixing the obtained

Sec-BuLi

1. THF

2. CI3C-CCI3.

of a bright red solution at -40 ° to -35 ° C for 1.5 h, a solution of 21.4 g (0.090 mol) of hexachloroethane in 125 ml of dry tetrahydrofuran was added dropwise. Allow the temperature to rise to -20 ° G. As the temperature of the reaction mixture was raised to room temperature for 16 h, the reaction mixture was treated with 200 ml of ice water plus 200 ml of saturated NaCl solution. The mixture was carefully acidified to pH 3 with concentrated sulfuric acid. Care is taken and the aqueous phase is extracted with 200 ml of ether. The organic phases were combined, dried over MgSO 4 and concentrated to give an oily residue of a dark yellow color. After chromatography on silica gel using ether mixtures in methylene chloride as eluent, the product (6.7 g) is obtained as a light beige solid, m.p. Mp 156-160 ° C. The IR and proton RPR spectra correspond to the set structure of the desired product. Sample recrystallized from ether. has m.p. 152-165 ° and is analytically pure.

Preparation of 5-Chloro-6- (4-isopropyl-4-methyl-5-oxo-2-imidazolin2-yl) -m-toluic acid

-95Example 19

Sec-BuLi

1 '. THF / TMEDA

2. C0 ₂

A solution miscible with 3.7 g (0.014 mol) of 2- (2-chloro-iotolyl) -4-isopropyl-4-methyl-2-imidazolin-5-one in 7θ ml of anhydrous tetrahydrofuran and 4.7 ml (0.031 mol) of N, N, N ', Ν'-tetramethylethylenediamine (TMEDA) in a nitrogen atmosphere was treated at -70 to -63 ° C by dropwise addition with 26 ml of 1.2 m solution of sec-butyl lithium (0.031 mol) in cyclohexane. After stirring for 2 h at -55 to -45 ° C, the reaction mixture was poured over 300 ml of anhydrous THF saturated with carbon dioxide. The mixture was allowed to stand at room temperature for 16 h and then treated with 25O ml of water and acidified carefully with ice-cooled concentrated sulfuric acid to pH 3. The aqueous phase was extracted with 150 ml of ethyl acetate. The organic phases were combined and extracted with 50 ml of 0.5 N NaOH solution. The basic aqueous solution was cooled to 5 ~ 10 ° 0 and carefully acidified to pile 3 with concentrated sulfuric acid, followed by a fine white solid as a precipitate. After

-94filtration, the solid was dried in vacuo at 54 ° G for 16 h to give 3.5 S of product, m.p. 240-245 ° C. Analytical Pure Sample of 5-Chloro-6- (4-isopropyl-4-methyl-5-oxo-2-imidazolin2-yl) -m-toluic acid, m.p. 245-248 ° C is obtained by recrystallization of the ethanol product.

Example 20

Preparation of 2- (5-imidazolidinyl) benzoic acids and esters

The methods described in Examples 9-11, 12-15 and 16-19 are effective for the preparation of a large number of substituted and unsubstituted 2- (2-imidazolin-2-yl) benzoic acids and esters which can be reduced to 2- ( 2-imidazolidinyl) benzoic acid and esters of formula II using sodium cyanoborohydride. Of the 2- (2-imidazolin-2-yl) benzoic acids and esters prepared according to the aforementioned methods are those described and given in Table I below.

-95o °

P, +>

00 cm m c- · * n so -j · I— CM »-» fH lili cm <r σ * o r «. cm m sr rH CM ι-M i-M

The compounds obtained by the procedures described in Examples 1-19 of structures:

(ί

CM

S

X X X

CM CM

X S X S

<£ *

CM CM

With X § X

0 0 0 0 CM CM CM CM z-s z- \ z ~ \ z— \ co £ co X CO., LTD X co X Oh 0 D C * -z C

δ δ δ δ

I co co co co ds δ δ S co co co δ x δ δ • H «$

δ) m

N §

(0

Λί • H h

P »β

C

Φ • P w

a β

β m

• H • d m

β • H faO

Φ

Ό

Φ p

ω β

ra φ

e

0) β

s φ

s o

N • H

CQ

H

ιΓ » Oh St and 00 rri m fri CM vO oo o m rri CO., LTD Oh CM | ^ ri | | —H | ^ ri r-l rri r — M m <r 1 m 1 CN 1 m 1 m 1 m 00 1 CN Fri. m 00 Oh en Fri. CM Oh CM Fri. rH r — 1 rri rH rri Fri. r-l

«3?

CN χχδχχχχχ

ΧΧΧΧΧΧΧΧ

Table I (continued)

m and and m m tn X X X X X X CN CN CN CN CN CN Oh Oh Oh Oh Oh Oh

ΧΧΧΧΧΧΧΧ X

310 0000000 O

CN

Q £ • CN CN CN CN CN CN CN CN CN CN

Z 'z “\ z ^ z ^ o §§§§§SSS δ δ δ 5 5 5 δ S 5 δ

I £? <*> co «Ιδδδδδδδδ δ =“ Λ οί en

X 5 χ χ m χ χ υ

Ό III ¹⁰ <λ Ά ο δ δ

-97ti

Ο «Λ V0 (·> cn 2 Oh »M 00 o ο CN ι ^ ΙΟ VO H CQ vO o un —H \ · CN CN τ — 1 r — 1 V_Z fH ι — 1 r — 4 CN '+ S • '· 1 1 1 1 1 1 1 1 1 <Τ m ο CN CO., LTD r — 1 in 1—1 r * o CN —Μ m VO vO X m Oh «J- r-l CN CN ι - 4 r-l CN \ -x rH r — 1 CN

o?

X X X X X S X O. O X X χ ·> AS you!> Ti • P to; ·

S · .:

H you o

»H rj

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m un m fO SC X, X £ b CN CN CN o Oh o X O X X Cm vS ·

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XX ΧΧΧΧΧΧ

SI o OOO o oooooo (S ¹

CN CN CN CN CN z *> z · ^ z * s / * \

X x a? T? -P

S δ δ § δ \ -Z S-Z \ »Z S-Z θ 'δ 5 S S S

CN CN CN CN CN CN CN / ->. Z * · *, Z—, z * »z- \ cn cn cn on cn cn δ δ δ δ δ δ> * ζ δ δ δ δ δ δ _ I 4Γ * £? on cn cn cn cn cn cn £ Ίδ S 6 δ δ δ.δ δ δ δ δ £? cn cn cn cn cn χχδδχ δχδχδδ

-98O

O •

• P «

• P \ o σ * o f * · en QooQenmo <rm

CM ^ -1 —I CM <- «\ O i — 4> —1 <—l l OM CM 05> -

CM l i l l i i i l i i i i i X l mo> <MOm <-unmcoooenv0CM <-i ·> —Ί <r, —i cm in • »Μταοι / ΊΓ-ισλ '· ^. ^

M 1-4. rt M 1-4 COf-li-4i-4CMf - ** - lr-4

1-4 00

CM Frt

S ¹

CM «M \ z- \ en en CN S S en en

0 _p mx en

C & j O O O O χ '-' χχχχχχχχχχ x

Table I (nasfcavak) .en

XXX en en en en xx.xxx'xx§§xxx X

31000000000000 o «S ¹

CMCM <MCM <MCM <MCMCMCM <MCM δδδδδδδδδδδδ δδδδδδδδδδ

CM en _ | £ 2l? IP £? Cncncneninenencn en οίΐδδδδδδδδδδδδ δ

-P 5? Huh? cn en m en χδδχδδχδχδχχ δ

99 “s ~ \ 'N' Ctf

P o

o •

• p

-P ep

X

CM m

sr r * co

CM

CM

Λ4 (0

P

ιΛ (Λ Γ Γ ιΉ rs σ * co ό <Μ CO., LTD | s 00 »A- Ό 00 \ Ο rA ο (Η. σ \ —Μ ι — J 1-4 CM UJ t — Μ CM ζΗ rH 1 ¹ 1 1 1 ¹ 1 1 Ο ΙΛ 00 σ> ο r- ~ SO m is sr \ Ο 00 m X \ Ο Ο * rs πΚ Γ- ( ΓΗ CM sz γΗ CM co I — t

n co n n

X X X x x X χ · S S S W £ p cp ep co co co δ δ 5 5 6 6 6

Table I (continued) cp co X X δ δ £ Ρ £ Ρ £ Ρ £ Ρ £ Ρ £ p co co cn δ δ δ δ δ δ δ δ δ

X X χχχχχ χχχχ

CM £ Ί δ

10 ο ο ο ο ο ο .ο οοοο

CM ζ- \ co δ

CM CM CM CM CM CM CM CM z-s z- \ z- \ Z * \ z-s z “\ z — s co x co R 8 CO., LTD X Mr Rücker CO., LTD S CO., LTD S co X in sz □ sz o □ c o Oh sz Oh sz C sz δ δ δ δ δ δ X o δ

CM

CO., LTD

Δ δ ι

η η Tj + § δ δ χ χ

III

-ΊΟϋ-

«- ( CM CM CM CM en 00 σ> Oh o> en CM en ιΛ o <· oo o fH fM CM rH f — 1 CM CM rH • • P 1 1 1 1 1 » 1 1 • -P 88 co en and — 1 o> CM m <r Mr Rücker m «5 · S rH and — 1 CM r — 1 CM CM

CM ft?

χχχχχχουχχχχ en en

S δ en en en

X X δ δ δ S S

I I <r <r

Table I (continued)

CM CM δ δ en en v- / en en oo δ δ ¹ 'δδχχχυυ en en en χχυ ^ χχχχδδδχχ

3IOOOOOOOOOOOOO χ ¹

CMCMCMCMCMCMCMCMCMCMCMCMCM

O. ^with * ^ o. ^z— '<>

S? ^'T. £?. £?. £? C'? Enenencnmcncn δδδδδδδδδδδδδ δδδδδδδδδδδδδ

And £ 42? £? £? £? £? £? £? £? £? £ 3 n «Ί δδδδδδδδδδδδδ lil co co co (* ι Ά η tn χδχδδχχδχδδδ

101o o

*

-P «

-P cn ca

o 2ϊ 2ϊ Vz CQ r4 s-z cn oo vO sr s S OO cn m r » cn \ O sr sr rH CM CM l “H r * 4 rH r- < 1 1 w ± * o 1 1 1 1 1 1 —4 sr m Ό S sr CM CM 00 CM CM σ> cn r ~ <r r-4 1— ( A i-H CM r-M 1-4 1— (

cn οδχυχχχχχ

I

CM cn X cn

Table I (continued)

I

CM

XX I ΧΧΧΧΧΧΧΧ cn cn cn χδδδχχχχχχχ

3Ioooomwwwmww e?

Ncmcmcmcmcmcmcmcmcmcm '<5; z— · O. O. z- \ z- \ z- \ z—. Z ~ \

JP m <n tn cn δδδδδδδδδδδ ** ** - ✓ \ »» Z \ _Z S ^ Z δδδδδδδδδδδ on tn cn cn £ Ί δδδδδδδδδδδ cm cm mz — s X cn m5 δ VP ϊ cn + 5,% δ S oi cn cn cn cn cm cn χ δδχχχδχδ δ +

102 · tšl rt

N rt

O o

«• P

P <£?

o 3 CM 00 ua ua cn r — 4

II and i

O un O ua

<r · * m σ> rrt CM ca -

Table I (continued) ► «

3 ca. W ca. 'CM CM CM CM / -> z «\ z— » z \ S ⁴ ca. K ca. K ca. £ ca. R oi U Oh S> · 0 0 s »z

δ δ δ S

I ca ca <2Ί S S ca ca

CH (CH3) 2 CH ₃ CH (CH3> 2 SHHHH 127-129

Na ⁺ CH3 CH (CH3) 2 SHHHH 175 - 200

For *! 2 CH ₃ CH (CH ₃ ) 2 SHHHH> 285

-103o

•

P

-P ω ω H H to ^^ csosi— i — I rH »—1 rH i— | rH rH f * H nH 1-4 <111111 m fh «s CN

I I I I <τόΗ®σ <] · Γ) οοίη§ en δ 4.

M en m C »g g

Table I (continued), ^x , ^xx co cn z * \ z- \

X X o δ en e ^ t en en t 1

I I

en en S ~ \ CN X <N X Oh \ _z D '-with

I I δχχχχχχχ χ

X *

Oh 0 0 0 0 W CN CN CN CN CN CN / —S. z ~ \ z- \ / —S en X en X en X <n X en X en X C \ -z Oh Χ-Ζ 0 </ 0 \ »Z Oh Oh ^ z

δδδδδδδδδδδδ _, | l? £? X? X? ^ ccnenenenenenen χΙ δ δ δ δ δ δ δ δ δ δ δ δ δ en en en en en χχδχχδδδδχχδ

X

-104-

o 3 218 • P 1 • «A- P r — 4 CN

rj © Ocnmmoomr-ivo - <CN CN _ | CM t — I r-1 r-l CN r- · r-l '> I I I I I I I I I I I £ 2 ?! CL vo — i O cn cn r- <o m dSS COOenr-HrMOm © i— 'CN CN <—ICN r-lr-lr-ICNi-li-l co cp

W W xxx xxxwxwxx

Table I (continued)

XXX = δ δ, X X X X X

CN CN <—> z- \

CN CN δ δ v t *. co O-I

II CN XX

X XXX ΧΧΧΧΧΧΧΧ

10 ooo oooooooo

CN

I

CN

CN CN z— \ z— »m m δ δ

CNCNCNCNCNCNCNCN z—> Z—. z->, x- \ z- \ / -χ cocncncncncncncn

S S δ S δ δ δ S

SS ^ δδδδδδδδ '-Z cn δ-δ sz fZ>, δ-δ * IS δ δδδδδδδδ x x J f ¹ χ δδχ χχδδδχδ

-105o

• • P • P

CO ca

M W W

H H H 03 osr-tmcNvjr-io ^ ocnr ^ ommeM

CM <—I —I I — I I-1 (- (r-1 r-1 r-1 c \ | r-1 CM I-1

I I I I I I I I I I I I I I I I jupmCTisoc ^ r ^ cMcoooscoOMf

Ο'ΟιΠ — I <f r-ITOChCMr * -O * l / 0 »ACM r-l CM i — I r-l i — I r-l r-1 r-l i — I r-l rM CM r-l

ΧΧΧΧΧΧΧΧΧΧΧΧΧΧ

CM CM CM

CM

CO b

CM

Table I (continued)

Ul

CM

CO., LTD

00 * r · X δ x CM 1 CM z- \ z-m CM R CM 0 x_z eO CO., LTD 0 x_z

OM

CM CM 'I Ul' x & x 8 x

CM

CO δχχδχχχχδχχχχχ

S | 03OOOOOWOWWWWOC / 3

CM

X

CMCMCMCMCMCMCMCMCMCMCMCMCMCM <3 'z- \ OO zm z \ z z \ with ~ \ z \ z \ £? F? £ Ocpfncococococococococo δδδδδδδδδδδδδδ δδδδδδδδδδδδδδ _ | £? XiXr> Fo £ OcpcpcpfOfO ro co co co'? L δδδδδδδδδδδδδδ <T £? £? op ep cp ep co χχδδχδχδδδδδχχ

-106Example 21

Preparation of trans-methyl o- (4-isopropyl-4-methyl-5-oxo-2-imidazolidinyl) benzoate

COOCH

II r

CH->

H (CH ₃ ) ₂

HN ——g

NoCNBHi

COOCH3 I H M CHi

'' CH (CH3) ₂

A stirring solution containing 27.4 g of methyl o- (4-isopropyl4-methyl-5-oxo-2-imidazolin-2-yl) benzoate in 200 ml of methanol was added one equivalent of 2M methanol HCl. Then 6.3 g of sodium cyanoborohydride and enough methanolic HCl are added to keep the pH at 2-3 · Two subsequent aliquots of hydride (4 g and 2 g) are added at constant monitoring and adjusting the pH of the solution to 2-3.

After stirring overnight, the pH of the solution was first adjusted to one with concentrated HCl then adjusted to pH 5 with 2N NaOH. The mixture was filtered, the filtrate was concentrated in vacuo and the residue partitioned between ethyl acetate and water, the organic extract was dried and concentrated. Trituration of this residue gave the crystalline solid, 15 g, m.p. 111-122 ° C. Purification of 7 g of this material by chromatography on silica gel using 40; ethyl acetate in hexane afforded 6.7 g of crystalline product crystallized from ether-hexane to give 5? 5 S trans-methyl o- (4-isopropyl4-methyl-5-oxo-2-imidazolidinyl) benzoate, m.p. 124-126 ° C.

Other compounds prepared by the above procedure are given in Table II below.

-107-

S

-p

ο Ο CM Ο Γ. ^ 4 r — ί CM CM Π CM ηΗ γΉ rH r — 4 r — 4 ΓΗ 1 1 1 1 1 1 Γ '» οο γ “1 S m f - 4 00 Ο CM <Μ CM ο ι— ( “—I CM 1-4 ΡΗ

Table II

ΧΧΧΧΧΧΧ x

SIOOOOOOO

CM CM CM CM <Μ CM CM CM ζ · \ ζ- \ ζ- \ Ζ “\ m m m m m m m m δ δ δ δ δ δ δ δ S- / S-Z S »/ χ-χ

δ S δ δ δ δ δ S im cn eo cn cn cn cn m E g g g g g i i ii δ δ χ δ δ δ

X *

-108Example 24

Preparation of methyl 3-fluoro-2-formylbertzoate

A stirring mixture containing 7.3θ g of 4-fluoro-3-hydroxyphthalide, 18.5 g of potassium carbonate and 11 ml of methyl iodide in 125 ml of acetone was heated to reflux for 2 h. After stirring overnight at room temperature, the mixture was filtered and concentrated. The residue was dispersed in 200 ml of ether, filtered and the filtrate concentrated to give 7.6 g of residue which was used directly without further purification. The NMR spectrum of this material corresponds to the expected structure of the desired product.

Example 23

Preparation of 4-fluoro-3-hydroxyphthalide

1. Sec-BuLi T. DMF

To a stirring solution of 10 g of m-fluoro-N, N-diethylbenzamide in 25O ml of THF under nitrogen at -70 ° C was added dropwise 52 ml of a 1 M solution of sec-butyl lithium in cyclohexane. After addition, 5.0 ml of dry dimethylformamide (DMF) was added dropwise at -60 to -65 ° C. The mixture was stirred for 1 h at this temperature and 50 ml of ice was added. The mixture was allowed to reach room temperature and stirred

-109 hours 2 h. After the addition of 100 ml of brine, the phases were separated and the aqueous phase was extracted with 150 ml of ethyl acetate. The combined organic phases were dried and concentrated to give 3.5 nes to bear two compounds, one being 3-fluoro-2-formyl-II, N-diethylbenzamide.

Upper aqueous phase after standing at. at room temperature overnight, acidify to pH 3-4 with concentrated _? 30 ^. The precipitate was extracted into ethyl acetate, the organic phase was dried and concentrated to give 8.5 g of a crystalline residue, which was crystallized from methylene chloride to give analytically pure 4-fluoro-3-hydroxyphthalide, mp 113-120 ° C.

Example 22

Preparation of methyl o- (4-isopropyl-4-methyl-5-thioxo-2-imidazolidinyl) benzoate

A stirring solution containing 5, C g methyl o- (4-isopropyl-4methyl-5-thioxo-2-imidazolin-2-yl) benzoate in 5 ml of absolute methanol is cooled to 0 ° C and 1.4 ml of concentrated HCl is added. The mixture was allowed to reach room temperature and 1.07 g of sodium cyanoborohydride was added. The pH of the mixture was maintained at about 3 by addition. 2M methanolic HCl. After 2 h. Further 1.07 g of sodium cyanoborohydride is added and the pH of the solution is maintained at about 3 · After stirring overnight, the mixture is cooled to 5 ° 0, concentrated HCl is added to give a solution having a pH of 0-1. The pH was then adjusted to 5-6 with 5M NaOH and

-110 Methanol away in vacuo. The residue was partitioned between water and CKL / H 2. The organic phase is separated, dried and concentrated. The residue was chromatographed on silica gel using 4: 1, hexane: ethyl acetate to give the product as a traveling component. Methyl o- (4-isopropyl-4-methyl-5 ~ thioxo-2-imide <azolidinyl) benzoa.t was obtained as a crystalline solid, m.p. 115-121 ° C. Analysis using the NMR spectrum indicates that this is mainly the cis-isomer contaminated with some trans-isomers.

Other compounds are prepared using this process using the appropriately substituted thioxo-2- (imidazolin-2-yl) benzoate as the starting material.

Example 25

Preparation of methyl o- [N- (1-carbamoyl-1,2-dimethylpropyl) formimidoyl] ~ benzoate

<f ^H3

NH ₂ ——— CONH 2 CH (CH ₃ ) ₂ cooch ₃ —CH = NH— <p — CONH ₂ CH (CH ₃ ) ₂

A mixture containing 5.0 g of methyl 2-formylhenzoate [C. Brown and M. V, Sargent, J. Chem. Soc. (C), 1S18 (1969)], and 4.0 g of 2-amino-2,3-dimethylbutyramide and 56 'mg of N-thioenesulfonic acid in 100 ml of toluene are heated to reflux in an apparatus equipped with a Dean-Stark separator for water for 3 h. The mixture was filtered and concentrated in vacuo. The residue was crystallized on standing and recrystallized from ether / hexane to give an analytically pure

-111methyl o- [N- (1-carbamoyl-1,2-dimethylpropyl) formimidoyl] benzoate, m.p. 79-80.5 ° C.

Using essentially the same process but starting with methyl 3-fluoro-2-formylbenzoate instead of methyl 2-formylbenzoate, the corresponding product, methyl 3-fluoro-2- [N- (1-carbamoyl, 2-dimethylpropyl) formimidoyl] benzoate, is obtained. tt 125-131 ° C.

Example 26

Preparation of cis- and trans-methyl 2- (4-isopropyl-4-methyl-5-oxo-2imidazolidinyl) benzoate

OOCH3

H = Nί ” ³ —con ₂

CH (CH ₃ ) ₂ ch ₂ ci ₂

TFA

A stirred suspension containing 4.14 g of methyl o- [N- (1-carbamoyl-1,2-dimethylpropyl) forraimidoyl 3-benzoate in 50 al methylene chloride under a nitrogen atmosphere and at 0 ° G was added 1.25 ml of trifluoroacetic acid. The mixture was allowed to stand at room temperature and stirred overnight. After cooling to 0 ° C, a saturated aqueous solution of sodium bicarbonate is added and a 7-8 pile is obtained. The organic phase is separated, dried and concentrated to give an oil which crystallizes the lagoon. NJ-1R spectrum of a sample recrystallized from acetonitrile, m.p. 143153 ° C indicates that the product is a mixture of cis- and trans-methyl 2- (5-isopropyl-5-methyl-4-oxo-2-ii: yidazolidinyl) benzoate.

Other compounds are prepared by the above procedure using

-112 suitably substituted 2-formylbenzoate in the process of Example 25 and using the obtained carbamoyl formimidoyl benzoate in the above process. For example, trans-methyl 3-fluoro-2- (4-isopropyl-4-methyl5-oxo-2-imidazolidinyl) benzoate, m.p. 98-104 ° C, can thus be obtained.

Example 27

Preparation of cis- and trans-methyl o- (4-isopropyl-4-methyl-5-thioxo-2imidazolidinyl) benzoate

<j * 3

NH ₂ - <p - csnh ₂ CH (CH ₃ ) 2

A mixture containing 4.5 g of methyl 2-formylbenzoate, 4.0 g of 2-amino-2,3-dimethylthiobutyramide and 20 mg of toluenesulfonic acid in 100 ml of toluene was heated to reflux using Dean-Stark's water separator for 4 h. The mixture was cooled, filtered and concentrated to give crystalline solid crystallized from Cl ^ Clg-hexane to give 6 g of analytically pure cis and tpans-methyl o- (4-isopropyl-4-methyl-5- zolidinyl) benzoate thioxo-2-imide, mp, 140-142.5 ° C. In this case, the trans-isomer predominates

-113Other compounds can be prepared by this process using suitably substituted 2-formylbenzoate. For example, using essentially the same conditions but using methyl 3-fluoro2-formylbenzoate as a starting material, cis- and transmethyl 3-fluoro-2- (4-isopropyl-4-methyl-5-thioxo-2-imidazolidinyl) is obtained benzoate, tt 115-123 ° C. They are similarly obtained

COOCH

Π3

HN

H CH ₃ N ^{Y 4} : h (ch ₃ ) ₂ where Z is OOH ^, tt 112-114 (mixture) and Z * SCH ^, tt 124-138 (mixture) Example 27-A

Trans-3-fluoro-2- (4-isopropyl-4-methyl-5-oxo-2-imidazolidinyl) benzoic acid is purified

To a warm solution containing 1.3 esters in 5 ml of methanol was added 2.5 ml of NaOH and the mixture was stirred overnight at room temperature. The solution was acidified to pH with conc. H ₂ SO ^. The mixture was diluted with 6 ml of water and ethyl acetate, filtered and the aqueous phase separated. Aqueous toluene, on cooling, precipitates the product as a fine white crystalline substance, mp 183-184 ° 0.

Using similar conditions and a suitable starting ester, the following acids are obtained:

-114ο ο

• • Ρ μ

CN ΜΟ οί <r

X Cn

IW co «S ⁴

CN CN z- \ co co δ δ s- '' s-Z δ δ cn m δ δ

Ο ο

• Η ΙΛ «5 (Μ ί>

cd cd 'O C! > ω> ο ο

Η

U ”,

Ο «ι> · - I υ | • Η ι — I • Η

COI • dl

Ο | m

σ \

P * »

0) • H co c C col OJ col OJ • d I P • H P ul 4J υ | JJ

σ>

ο r *.

r *

Ό σ>

m r *

XX X X X b «

CN δ x «Ή tu

XX X X X

O O C / 5 W O

CN CN z- \ z “\ cn m δ δ v-z ^ -z δ δ

CN z- \ cn δ

ζδ

CN m

δ s-z δ

CH (CH ₃ ) ₂ m cn δ δ co

-115Example 28

Preparation of methyl 2- (4-isopropyl-4 ~ methyl-5-oxo-2-imidazolinyl) nicotinate

This method involves the formation of tricyclic compounds

A mixture of 25 g of amide and 1 ml of 1,5-diazabicyclo- [5.4.0] undec5-ene (DBU) ΰ 5θθ ml of xylene was heated to reflux for 1 h using a Dean-Stark water separator. The mixture was cooled, the aqueous separator removed, 100 ml of anhydrous methanol added and the mixture heated to reflux 1h. The solvents were removed in vacuo and the product was isolated by chromatography to give 13.65 6 products, m.p. 120-122 ° C. The other esters are prepared in the same manner as above, using a suitably substituted amide as starting material, This process is also described in · European Patent Application 81103638.3 Publication Number 0.041,623.

-116Example 29

Preparation of methyl 2- (4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl) nicotinate

A mixture of 13.65 g of nicotinate and 9.69 g of phosphorus pentachloride in 110 ml of dry toluene was heated with stirring to 80 ° C. After 1.5 b, the thick mixture was cooled, filtered and the solid was washed with ether and dried, Hydrochloride was awarded salt of the desired product.

This salt was dissolved in 60 ml of water; neutralized with sodium bicarbonate, the resulting precipitate was separated by filtration, washed with water and air-dried to give the product:

AV-COOC ^ rHj

II ^J 1. PC1 ₅ / POC1 ₃ ^ Λ-conh— <j: —conh ₂ ηπηζόCH (CH ₃ ) ₂

A mixture of 5.0 g of nicotinate and 7.1 g of phosphorus pentachloride in 40 ml of phosphorus oxychloride was stirred at room temperature overnight, the phosphorus oxychloride removed in vacuo, the residue suspended in 40 ml of toluene and concentrated again, This process was repeated. 40 ml of water was added to the residue and the mixture was heated to reflux for 1 h. After cooling, the mixture was extracted with methylene chloride, the extract was dried and concentrated to give 1.05 g of the desired product, the pH of the aqueous phase from extraction with methylene chloride was adjusted to 5-6 with sodium carbonate solution and the mixture was again extracted with methylene chloride. The dried extract was concentrated and the residue crystallized to give 2.65 g of the desired product,

Using one or more of the methods described above, the following nicotinic acid esters are obtained:

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-127Example 29-A

Preparation of ethyl 2- [2- (dimethylamino) vinyl 3-5-nitronicotinate

C00C ₂ H5

J-CH3 (CH3) 2NCH (0CH _{3) 2}

N

A solution containing 20.88 g of ethyl 2-methyl-5-nitronicotinate in 100 ml of 1,1-dimethoxytrimethylamine was heated to reflux for 3 h and 15 minutes. The mixture was cooled and the solid was collected by filtration, washed with methanol and air-dried to give 26 g of the desired enamine as a dark red solid, m.p. 176179 ° C.

Example 29-B

Ethyl [N- (1-carbamoyl-1,2-dimethylpropyl) formimidoyl

5-nitronicotinate

l> —CH = CH — N (CH ₃ ) ₂ N

0 ₃ , (CH ₃ ) ₂ 5 <fH ₃

CH (CH ₃ ) ₂

CONH 2 CH (CH ₃ ) 2

-128 A solution containing 18.9 6 enamines in 200 ml of CH ^ Clp and 10 ml of methanol cooled in an ice bath is introduced with ozone from a Welsback Ozone Generator operating at 120V and an air pressure of 55.2 kPa. enamine red color. Ozone is then replaced with nitrogen and 10 ml of dimethylsulfide are added. After 15 minutes, 9, θ 6 of 2-amino-2,3-dimethylbutyramide was added,

J ». transfer the reaction mixture to a 5θθ ml balloon and concentrate. The residue was dissolved in $ 00 ml of toluene and heated to reflux under nitrogen and using a Dean-Stark water separator. After 1 h, the solvent was removed and the residue, which was mainly Schiff's black rubber base, was used without further purification.

Example 29-C

Preparation of cis- and trans-ethyl 2- (4-isopropyl-4-methyl-5-oxo-2imidazolidinyl) -5-nitronicotinate

The crude Schiff base described above was dissolved in 5θ ml of CHgClg and treated with 4.6 ml of trifluoroacetic acid (TFA) at room temperature. After 1 h and addition of 1 ml of acid, stirring was continued for 1 h. The mixture was cooled, 5.5 6 sodium bicarbonate was added. After gentle and careful addition of water, stirring was continued until CO ^ development ceased. The pH was adjusted to 7 with saturated sodium bicarbonate solution and the CHpC4 layer was separated. The aqueous phase was re-extracted three times with CHgCl-β. The combined extracts were dried and concentrated to give the crude product as a dark colored semi-solid. This material was chromatographed on silica gel using hexane-ethyl acetate mixtures to develop and elute the product. Trans-ethyl 2- (4isopropyl-4-methyl-5-oxo-2-imidazolidinyl) -5-nicotinate is eluted

-129 first, then recrystallized from CH ₂ Cl ₂ -hexane to give pure trans-

TFA

The cis-isomer is subsequently eluted and recrystallized from CH ₂ Cl ₂ hexane to give pure cis-ethyl 2- (4-isopropyl-4-methyl-5-oxo-2-imidazolidinyl) -5-nitronicotinate, mp 149-150 ° C. .

Example 29-D

Preparation of methyl 2- (4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl) 5- (methylthio) nicotinate

To a stirring solution containing 1.0 g of bromine compound in 5 ml of TUF and 2 ml of DMF was added 210 mg of sodium methyl mercaptide under a nitrogen atmosphere. After 2 h at 60 ° C, the mixture is cooled to room temperature> ** »

-130 hours, adjust the pH to 4 ea with acetic acid, pour over ice and extract with 2 x 50 ml of ether. The extract is dried and concentrated,

NqSCH ₃

THF / DMF

a yellow oil is obtained which solidifies slowly, Recrystallization of this solid from ether / hexane gives pure methyl 2- (4- isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl) -5- (methylthio) ) nicotinate, tt Mp 107-108 ° C.

Example 5θ

Preparation of cis- and trans-methyl 6- (allyloxy) -2- (4-isopropyl-4-methyl · 5-oxo-2-imidazolidinyl) nicotinate

A solution containing 7.0 6 (22.1 mmol) methyl 6- (allyloxy) 2- (4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl) nicotinate in 7θ ml of absolute methanol is cooled to 0 [deg.] C. and a few drops as indicated by methyl orange, and 1.8 ml (22.1 mmol) of concentrated HCl were added to the stirring solution. Red the solution was warmed to room temperature and 1.4 g (22.1 mmol) of cyanobophyde sodium was added, and the solution was slowly returned to orange.

-131 color (pH about 4), then 2E methanolic HCl was added to the mixture as long as

H * does not appear red (pH about 3) · This is a pH adjustment procedure

NoCNBH ₃

it is repeated until the color changes for a long time. After stirring overnight at room temperature, the solution was cooled to 0 ° C, the pH adjusted to about 0 with concentrated H01 to decompose residual NaCNBH ^ · The pH was then adjusted to 5-θ with 5 M NaOH. The methanol was removed in vacuo and sufficient water was added to the residue to dissolve the inorganic salts. This mixture is well extracted with CHpOlp, the extracts are dried and concentrated. The residue (about 7.8 f) is a thick oil which is chromatographed on 35θ 6 silica gel. Using 1: 1 CH2Cl2-hexane and then the ether as eluent is obtained in the separation of 0.35 S starting material. Further elution with ether afforded 1.87 g of the trans isomer while isolating, and further elution with $ 10 methanol in ether gave

-1325.2 g cis-isomer

The trans isomer is recrystallized from GH ^ Cl ^ hexane to give 1.16 g of analytically pure trans-methyl 6- (allyloxy) -2- ( ^with t-isopropyl-4-methyl-5-oxo-2-imidazolidinyl) nicotinate, mp 144-142 ° 0.

Similarly, recrystallization of the cis-isomer from Cl ^ Clp-hexane yields 4.6 g of analytically pure cis-methyl 6- (allyloxy) -2 (4-isopropyl-4-methyl-5-oxo-2-imidazolidinyl) nicotinate. tt 120-122 ° C.

Using essentially the same process but substituting suitable 5-oxo- or 5-thioxo-imidazolinyl nicotinate instead of 6- (allyloxy) -2- (4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl ) nicotinate, 5-oxo- and 5-thioxoimidazolidinyl nicotinate are obtained.

Other compounds prepared by the above procedure are described in Table III below.

v

-133H • H

G -P • H ctf O Ό G O • rl> rl · ι — I-P -P O O · «Λ4 -P 0 $ Ή X) G • rl S H

CM rH

I

Oh

CM oo • H

Oh

I θ '

Oh

Preparation of 2- (2-imidazolidinyl) nicotinate

H • H P »• S ssrM Ή · O -P -P H O ·« Λί-Ρ Ό · Η • g *

H

N | n o cn oc

CM in sr cm o i

O «

r-4 m

XXX

XXX

XI XXX

OOO

CM cn

ΙΛ Š <

N χ cm O D X cn cn δ δ «cn δ-δ δ

(II cn cn cn δ δ δ οέ |

-134H • H β

• H

O cO O • Η βθ Η · Η, ΟΨ> ψ> NO. · ΦΛ4 43 • Art · Η • Η β S Η

Η ...

• Η Λ Ο rl β Ο Ο 'Γ + Ν43 β Ο • rl * rl ββ Η • 43

C0 | * »Η I υ s- \ β

ω φ

Å ra m

1 — AND AND!>.

st

ο σι 0 Ο Oh Oh Oh • « • • • • • ο co 0 st 0 0 CN ΙΠ f * · m st CN st rri rri rd rd rd rd rri

I I I I I I I I I

Ο m ΟΟΟΟΟ • · · · · · ·

Γ '· 00 rd 00 CN 00 00 rd h * * ί \ J r> ^ CH

Table III (continued)

N |

XI X X ΧΧΧΧΧ

O O OOOOO

I I st

St m oo S ~ \ <0 <0 co χ X CN X X X CN CN δ O 0 0 0 Oh

co co co m m co δ δ δ δ δ δ-δ δ-δ £ l

III%

δ

III and m%% Π.

-135H • rl rt • rt P • d rt o • rt rt Q f — t · Η ·

O P «O rt • d-rt • d«

E H f-1 • rt P rt rt • H rt o r-t «rt O O -P« O rt .M • d «rt • g

H

P • P rti m-i u

o%

And o

• cr oo m

oo

Oh o Oh m • o • • · • • MO CN <r Γ * » CN CN CN rH 00 rH “—I rH

lili o o o o .... m <f m cu oo cn cu

Table III (continued)

N |

XI

XI cu

Z- \ on cn b

n « n. Px n- n · X X X X X cn cn cn cn he Oh U in o U « 1 1 1 1 c C c • M • rH X X X X X

X X X X X X o o o o o Oh CN CN CN CN CN CN / —S Z — s z—> z ~ \ s- \ cn X cn £ cn £ p cn X cn X Mr • 0 Mr Mr v »z C v_z

<21 δ S S g S δ δ δ on rt δ on on δ δ on on on on on δ δ δ δ δ

CN ζ ~ \ on _ <cn cn cn χ on>. . _ δ δ δ οδδδυ m on χ

-136rH • H d +?

• H rt d rt O • H «HO H« P · O O -P NAi · rt -HP, • d d • H s

H o

•

CO pp pp

I m

Ό m

«

CO., LTD

CM (0 • H

U

I

CO., LTD

And o

and — I m

i ** «ΟΡΗ

I

Oh

O O • ·

S 8

Pp Pp

I I

O o • · p CM o ov co

CM pp

I

Oh

CM

ΌCM

CM pP »

Oh

Table III (continued) iH • H-P d d • H d o H «HO op ·« op rt Λί · • ϋ'τ «p • g"

H

N |

XI .Sl

m fH and <r Pp σ fp pP S f * 4 m Oh iA Oh Oh o o m o • • • • m • « • o • • o o st • CO., LTD co o • CO., LTD ov l-P r * co vO r * » pp CM σ CM pp pp pp pH pp ov pp fH pp αν pp pP 1 1 1 1 1 1 1 1 1 1 • m o Oh o m o o Oh o Oh Oh • • « • • • • • « • « VO o αν CM m o Ov vO o * Oh f · '· CM vO ov fH R4 co OV 04 Pp pp f — 1 fH

r * ·

3 »o

I I • n m χ

CM

With co δ

m m m X X X CM CM CM U U Oh

«, CM and m χχχχχυοχ

ΧΧΧΧΧΧΧΧΧΧΧ ooooooooooo

CM CM CM CM CM CM CM CM CM CM 04 z- \ z— \ z—. r \ / p z «s z—> z— \ x * \ co co cp CO., LTD X * co CO., LTD co CO., LTD CO., LTD n e δ δ δ δ δ δ δ δ δ δ s-z K.Z V- / · > / > «Z

£ 1 δδδδδδδδδδδ

CM m m cofpkpX ^ 4r> pX'X'X '

5, δδδδδδδδδδδ

CM z “\

CO., LTD

CM 'K co oi __ COCOCOCOI ^ -ZCOCOCMCO δδδδδδδδδδδ

-137H • H • S s * d c o • H «HO H -P ·, O O -P ΝΛ4 · d-H -P d.« • H a ·

H • H + 5

They are p4 · Η0 OP · «O -P

534 • g ”

H

CO., LTD

1-4

U

About a

I

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CM o

I m

m <n σ \ m

and o

Ό m

rti o

Š

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•

CM

Ό σ * m

And o

• oo m

CM <T

Ο 00 ο 00 Ο Ό m m ο ο o o • cm; • ο • f *. « « • • m • • • m « ί- ^ ♦ ι / Ί Ο \ κθ • cn 00 rti Ο m ο CM 00 ρΗ rti m rti o Ρ-4 CS 1—1 F-4 —4 ι — Η rti rti rti 1-4 1 + 1 + 1 1 1 1 1 I 1 1 •

o o o o o o m> L O IL o • O · Q · o cm zX o 'cm —r sj · ί—, <t <® it

1-4 β O O O S 00 —I —4 CM MO

About Γχ

H o

Table III (continued)

N |

XI

CM

Z1 m

iA

XX X_ XXX < ³⁵ σ '

X θ '

CM CM CM CM CM CM CM CM CM CM z- \ Z \ / -X ZM 1—> z \ z-x m cn m cn cn cn cn <n cn cn δ δ δ δ δ δ δ δ δ δ .Χ-Ζ Χ-Ζ χ-χ > -✓

δ δ δ δ δ δ δ žl δ δ. 42 £ 2 £ 9 cn cn cn cn cn cn cn

Sl δ δ δ δδδδδδδ α: Ι νΠ%

CM s ~ \ cn m

8.

H ♦ H rt p • H rt tj rt • H -HO H P. · 'OOP ga · «• d p tj rt • H S H

H P β rt • H rt P H-rlO O P »· N O rt tj -rl • rl fi s

H • P +>

o a rH Oh • m CM f-h m S r-l 1 1 1 Oh o o • • • CM co CM CM CM CO., LTD and — 1 and — 1 r-l

Table III (continued)

N | > 1

XI <21

I I <r o

CM δ · νχ m s-s l_i

I --- I sr

X ”\

CM δ

* - 'co δ-S

In —- and sr 'z- \

CM δ

co δ-3 £ l co c

lil%

X o

CN rd • H

C -P • H bJ ύβο • id · ΗΟ H -P · OOP NM · «• rd P • d c!

• H a

H rd • rd P

a. «o • H PP rd id-. · OPP NO ·« MP d-id • rd P!

a

H co * o c

CO sr co • n About CJ ·

Ό sr

O O O O • · «· σ» cn o cn 00 CN r-l rK

CN \ O n * I— «O 00 00 CN

I I

O O • · © o o m • ·

CT »1—1 cn m ι — I r-t I I

O o • · p * σ »cn <r m o • · cn r * <r m i i

O o «· cn m sr m r-ι O» n sr. .

• σ »rr» o cn

CN ι — I ι — I + I I

IL o O «· <—i m m o © cn

Table III (continued)

N | cn

M | X X X X X X XX

CN CN CN CN CN CN CN z— » ζ · \ z-s x- \ zs cn cn cn cn cn cn cn δ δ δ δ δ. δ δ > -✓ K— / v-z

£ i δ S S δ δ S δδ cn co en en cn en cn ep δδδδδδ δδ

en cn cn cn cn cn cn <n m δδδδδδ δ δ • rl c

'• d Je • H β o r4' rlO O P · N O -P ti Al · Ό · Η -P • H β E H

H • H +> g ti • H β O H-rlO 0-P · N O -P with · s °

H

CO • rl I cj

Oh Oh o . · • • Oh Oh CN m • Oh cn m —4 —4 rH Φ Φ 1 1 1 T3 Π 1 Oh Oh Oh r — 1 H Oh • • • 3 3 • r * o cn cn o cn r » i-H

Table III (continued)

NI X X X X X It is not X X X X X cn N | X δ X X X 31 o o o o o CN CN CN CN CN cn Z * \ cn Z “\ m z * \ z * s m cn δ δ δ δ δ -Z (Fig δ δ δ. δ δ <21 cn cn cn cn cn δ δ, δ δ δ

from

A i

¥ δ »N δ δ νϊ

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S £

5-141-0rH • Η β -µ • Η β β β. • Η · ΗΟ Η-Ρ Ο Ο Ν Λί β · Η • β β • Η 6 Η γΗ · Η + »β β • Η β Ο ΗτΙΟ Ο -Ρ · NO · Ρ βΛί · • β-Η -µ Ή β s

Η

Φ Φ Φ Φ Φ Ό -Γ3 · Π> · Π> Τ3 Η Η Η Η Η β β β β β

Μ ' Ν | X X X X X β δ ^: • μ. 03 β β ο > «Ι X X X X X

Η

Η

Κ β

Ο • Η

et 'β Η XI X X X X X 31 Ο ο ο ο ο CM CM CN CM CM ζ “\ ζ—> ζ “\ ζ> ζ- \ en X en Κ en Κ en X m χ □ Ο 0 ν-ζ Ο \ -ζ Ο S δ δ δ .δ δ

«ΣΙ

CH σι σι η η δ δ δ δ

: -3A2-

Η ω c • Η <0 β +3 Ρ • rl <ΰ Ό β Ο • Η · ΗΟ 4J dazol nikot m.p. • Η Β C0 • Ρ Η υ

β aJ ΉβΟ H-HO O-P N o -I (β -M Tj-H 4 • H β B

H

ο o Oh o Oh o • • • • o • • m 00 en 00 9 m vO r4 en en o O. en 04 rH fp Ip rM σν Φ rH 1 1 · 1 τη 1 1 ¹ Γ + 1 Ο Oh un Oh o β Oh m • • • • • • • rH vO <5 m en 04 r4 en m σ> en 04 <P rH p » fp

Table III (continued)

N | > 1

XI a

«UsI

ΧΧΧΧ

X X X X X X X X Oh o o o o o Oh o 04 04 04 CN 04 04 04 04 ZP ΖΛ ZP zp zp ZP zp zp en X en £ en £ en n en R en ?! en ?! Oh s-z Oh sz o C * -z c s_z Oh 0 \ _z D \ _z

δ δ.δ δ δδδδ ep ep ep ep ep en en δ δ δ δ δδδδ

• H β

ΉΡ • d «5 • h5 o Γ-Μ.Ο OP ·. tMO «544 d-H • H a β H pM • H P ϋ« S • H β O ι-f · ΗΟ, OP «O

H • 1

P

H β

ο Ο Oh • ο « Ο • • 00 • CN rM r *. sr os CN φ Γ * Φ φ I — t r » το · Γ3 • ο 1 ι ρΗ rd 1 ι 1 3 Ο ο β β Ο un o • • • • • 00 cn Μ0 r- r * ο r * sr r * »-M ι - 4 f - 4

i

O •

m rH fH

O <£

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• m

os m

•

CM

About pM

I

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Table III (Continued)

N |

X X X X X X X <21

X X X X X X X X X X o o o o Oh o Oh o Oh o CM CM CM CM CM CM CM CM Z — s z— \ z ^ z ^- ^ z— \ s- *. z—> cn cn cn cn cn cn cn cn δ δ δ δ δ δ δ δ s «z s »z > * ✓ s-z 1 v ^ z 1 > «Z δ δ δ δ δ δ m / ·> δ un z> δ CM CM δ δ v-z cn cn cn cn cn cn 1 cn 1 cn

s s δ δ δ δ m

X

CM cn š, sr z ^

CM δ

z—> n δ

A

I

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CM?

In 2 δ

CM

CM z − s cn δ

un x

£. , _ _ .. CM CM C δ 3 δ δ δ δ δ

04 |

-144— o

CM

H • H β +?

• H ClJ d β o • H -HO H -P · OOP n, y * «0 · Η P Ό β • rl a

H r- * <r

CO I —4 υ

I

O vO <T iH • H P β OJ • H 5 O H-H O OP - «I N O, P d 44 · Ό · Η P | • H β a

H o o o »n« · · «oo cm m m <- · n r * co (JS I-H (—l F-t §111 there © <r oo m cm» - * cm vo m o

g —H

I

Oh

S

O un in o O o <r vo m rcm vo -h en in CM cm vo

And o

•

CM

CM

I I I m o o • · · <r <r un vo i— en

Table III (continued)

NI

ΧΧΧΧΧΧΧΧΧΧΧ

ΧΧΧΧΧΧΧΧΧΧΧ en χχχχχχχχδ

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S

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z ~ \

CM and un '-z un, £ Γ <ΓΧ. en X en en £ t iS δ ¹ S 5. USS δ OSS

“I — I en z” s on

N m «_ x un υ 15, Ο X z- \ CM Q vb en X 'A g a

III / $ g g en ιίι ιϊι £, δ · &% en z- \ en en en «I 55555ο5δδδ? 5

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ZS

S .:

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rt

G 'szH

H

H rt

O • H

H

JO rt

H

H c • H rt Mr P • H-P • b rt in • Γ »Π Oh H -r} 0 O-P- • N O • P • • 6 «rl P • H G e co H U

H • H-P G rt • H G Oh A-H O, O -P • N O cape X • -drl 0 H «. H

N |

XI

XI «Sl sl and ο

cn ι

un σό

CM

Ο

S zS

I

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un

Oh Oh Oh Oh o o CM • m Oh o • • • • • • • • • rH * —1 cn m 00 CM 00 (S cn <n rH un o> rs i-M rs σ * m iS rH rH r · i Φ Oh 1 1 1 1 t 1 t 1 1 1 A o cn m Oh o o un Oh Oh o P • • • • • • • « • • m rs vO \ O CM 00 00 <r o> rs rs <T> and CM CM un «H zH ^ 4 r-4

cn χχχχχχχχ X § χ

ΧΧΧΧΧΧΧΧΧΧΧ

ΧΧΧΧΧΧΧΧΧΧΧ

Oh o o o o o o o o o o CM CM CM CM / n cn X CM CM CM zs cn CM CM / S zs ZS Oh zs zS X ' zs zS m cp cn sz cn 0 cn cn δ δ sz δ \ -Z 5, δ δ sz δ s- / δ

sz sz s / cn s · sz u \ _x s_z sms ssYYs δ cn cn cncn cn cn cn cn cn

565555835 / \ cn cn δ δ c i

m rH

X rs O i

Y>

c i «n rs χ rs cn so χ cn c

i o \

X

J

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X sO%

III δ δ S cn cn, cm δ'δ

-146ta §

H.

K

H id O • rl; r-1

Ed • rl ΰ

• η -μ, τ! ( ^Η ο 5ο °

Η Ο Ρ ΚΙ Ο

1 ^ΰ

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ον

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o o o o m • ' UO • o o • • • From • and • • r *. m From From 1 ^. From m <r m 0 * he rH ON (—1 NO 00 1 1 1 1 1 1 MZ • n> 1 1 Oh • o • o • m o • Oh • H 2 Oh • o •

m cm m o *

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XXX

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tort

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H rt.

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P

H P id rt H CJ o H HO Op · N O P rt JM · • d H P • H d a H

H P d rt • H d o H HO O P NOJ rtj4 • d H -I H d (0 • Fa u

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Oh o o o o 43 d r- d 00 and — 1 CM os ra ra r— * and — 1 and — 1 ra 1 1 1 1 1 Oh Oh Oh o o «R d S d r-. zH “-I for ca. zH zM ra ra Oh Oh o ua « • • * f-4 ra s m Oh 8 1—) ra ra 1 1 1 1 1 o o o o d d ca. Os CM oo o OS ra zH Oh Oh o o Oh • « • « « rrt ua s r » o ca. Oh «-Rt ra «- < —M t 1 1 1 1 Oh Oh Oh o Oh σ \ ca. ua ca. ua o Oh ca. 00 Oh «-Rt ra —4 ra X X X X X

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CM xl χ χ G% δ £ žl s o

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X X X X X X X X Oh o o o o o o o CM CM CM CM CM CM CM CM Z \ z-s z- \ z ~ \ z — v z—> z “\ ea K fi ca. R p ca. X ca. X ca. X ca. X 0 \ -z C 0 □ S 0 s — t 0 s-z CJ δ δ δ δ δ δ δ δ

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-148Example 31

Preparation of cis- and trans-5-ethyl-2- (4-isopropyl-4-methyl-5-oxo2- (imidazolidinyl) nicotinic acid

Miscible slurry containing 2,89 g of 5-ethyl-2- (4-isopropyl4-methyl-5-oxo-2-imidazolin-2-yl) nicotinic acid in 20 ml

00H

N

CH3

CH (CH ₃ ) ₂ = 0

NoCNBH ₃

C2H5 — COOH

HH CH ₃ ίζΝχ *: h (ch ₃ ) ₂

HN - 1 = 0 methanol and one equivalent of 2M methanolic HCl were added 0.6 g of sodium cyanoborohydride under a nitrogen atmosphere. Methanolic HCI was added to maintain the pH at 2-3. After blurring, the pH of the mixture was adjusted to 1 with concentrated H01 and after 15 minutes, the pH was adjusted back to 3 with a saturated NaHOO solution. After filtration, the solution was extracted with ethyl acetate. The pH of the aqueous phase was adjusted again to 3 and extracted again with ethyl acetate. A crystalline precipitate of cis- and trans-5-ethyl-2- (4-isopropyl-4-methyl-5 “Oxo-2-imidazolidinyl) nicotinate was formed and recrystallized from ethanol to give the product as a crystalline solid, m.p. Mp 208-210 ° C.

M *

It contains about 66% of the cis- and 34 ·% trans-isomers of Example 32

Preparation of cis-6- (allyloxy) -2- (4-isopropyl-4-methyl-5-oxo-2imidazolidinyl) nicotinic acid

A solution containing 3.9 6 (12.2 mmol) of cis-methyl 6 (allyloxy) -2- (4-isopropyl-4-methyl-5-oxo-2-imidazolidinyl) nicotinate in a minimum volume of methanol (about 15 ml) is added

12.2 ml of 2N NaOH solution, a precipitate is formed and the mixture is heated under stirring to 45 ° G, which is maintained at 1 h. Solution · -149 becomes clear. The mixture was cooled to 0 ° C and 12.2 ml of 2N HCl was added. the solid precipitate was collected and washed with ether and dried in air. This one

the material (3 »2 g) was recrystallized from methylene chloride-hexane to give 2.3 6 analytically pure cis-6- (allyloxy) -2- (4-isopropyl-4-methyl-5-oxo-2-imidazolidinyl ) nicotinic acids, tt 193-194 ° 0.

Using essentially the same process but using a suitable methyl 5-oxo or thioxo-imidazolinyl nicotinate or quinoline-3-carboxylate instead of cis-methyl 6- (allyloxy) -2- (4-isopropyl-4-methyl-5-oxo-2 -imidazolinyl) nicotinate to give the following 5-oxo or 5-thioxoimidazolidinyl nicotinic or quinoline-3-carboxylic acids. The reaction is illustrated using nicotinate in the reaction.

--150o ^q ra ra ra

S ra ra ra ra • rt * rt rt υ υ υ ra c

ra

P jj ra ra ra m • rt «rt * rt 'rt υ υ u u ra g

in

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ra

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4J «S this φ

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CN 00 40 o rrt CN I o

cn 04 <o O O «n CN CN 1-4 r * o

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a co co c

co μ

m - CN 5 CN CN co • rt υ

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CN CN cn cn XX, CN CN> · o υ mm B 6 χ xmm δ δ oo Ul! ^{5 δ} κίχχχχχχχχχχχχχ

3ΙΟΟΟΟΜΟΟΟΟΟΟΟΟ

CN CN CN CN CN CN CN CN CN CN CN 04 Ζ - 4 4 “4 z “s 4 ~ 4 Ζ - 4 <- < Ζ-4 rtS Ζ-4 4 “4 Ζ-4 <η cn cn cn m cn m cn <η m cn m δ δ cn δ δ δ δ δ δ δ δ δ δ Srt χ-ζ X Χ-Ζ χ-ζ > -ζ Χ-Ζ χ-ζ ΧΖ χ-ζ χ-ζ χ-ζ δ δ CN Ο δ δ δ δ δ δ δ δ δ δ

.mmcnmcncncncnmmmmm «? And δ δ δ δ δ δ δ δ δ δ δ δ δ

Acid t.t> ·

-152N |

0) § b jj (0 • s b jj ω • H U co • K U co • K U Oh Oh 0 Oh Oh and and CM and 8 m Oh —4 * 3 · CM 1 CM CM 1 Oh CM CM 1 0 1 0 1 m 1 0 « • • • • a s cn < 00 os CM CM CM CM CM CO., LTD zn S cn R A 0 X X Z X

CM CM

z 1 0 o o o o o CM CM CM CM CM CM zn zn zn zn zn z> Mr Rücker cn K Mr Rücker cn R cn K cn «C «2Ί Oh V-Z δ D S-f δ 0 S- / δ 0 ^ _z δ 0 v — z δ C nz δ cn cn cn cn m m * 1 δ δ δ δ δ δ

-153Example 33

Preparation e cis-methyl 2- (4-isopropyl-4-methyl-5-o ^ ^the ~ 2-imidazolidinyl) nicotinate hydrochloride

To 2.0 g of cis-methyl 2- (4-isopropyl-4-methyl-5-oxo-2-imidazole idinyl) nicotinate was added 25 ml of 2N methanolic HCl. The solvent was removed in vacuo and the residue was crystallized from ethyl acetate-ether to give the hydrochloride salt, m.p. Mp 189-192 ° C. Other acid addition salts are prepared by the above process using suitably substituted 2- (2-imidazolidinyl) nicotinate of formula III.

Example 34

Preparation of sodium 5-ethyl-2- (4-isopropyl-4-methyl-5-oxo-2-imide -

-154U A solution of 0.14-98 g of NaOH in 20 ml of absolute methanol is added to 1.0 g of 5-ethyl-2- (4-isopropyl-4-methyl-5-oxo-2-imidazolidinyl) nicotinic acid. under nitrogen at room temperature overnight, the solvent is removed to give a solid which is dried in a vacuum oven at 60 ° for two days, sodium 5-θΐί1-2- (4-isopropyl-4-methyl) thus formed -5-oxo-2-imidazolidinyl) nicotinate dark at 230 ° C and decomposed at 24-7-25O ° C.

Example 35

Preparation of cis-methyl. 2- (4-isopropyl-4-methyl-5-oxo-2-imidazolidinyl) nicotinate cooch ₃ f ” ³

CHO pTSA

NH 2 - <j: —conh ₂ CH (CH ₃ ) ₂

A solution containing 1.24 g of methyl 2-f bromine 1-pyridine ~ 3carboxylateaf (Bull. Soc. Chem, France, 36, 78-83 (19θ9) 3ι l, og 2-amino-2,3-methylmethylbutyramide and 20 mg p-toluenesulfonic acid (pTSA) is heated to reflux under a stream of nitrogen, and a certain amount of water is extracted in a Dean-Stark separator for 6 h, the solution is filtered while the hot filtrate ends up in a vacuum leaving dark oil behind The oil was extracted into ether, the ether evaporated to give a yellow solid, which was recrystallized from hexane-ether and methylene chloride to give cis-methyl 2- (4-isopropyl-4-methyl-5-oxo-). 2-imidazolidinyl) nicotinate, mp 118.5-120 ° 0, identical to that of the products obtained by reduction of methyl 2- (4-isopropyl-4-methyl-5-oxo-imidazolin-2-yl) nicotinate by sodium cyanoborohydride. trans-isomers were determined by NMR spectroscopy. The following procedure and using suitably substituted 2-formylpyridine-3-carboxylate gave 2- (2-imidazolidinyl) nicotinic acids and esters of formula III are given in Table IV below.

v

-156-

n 0) n n 01 n M. - » · - Oh Oh o o o

o o o °

P o o o • · · cn a- c—

Preparation of 2- (2-imidazolidinyl) nicotinic acids and esters of formula ΪΙΙ

I I and o • · co r ~ - o

I I o o σΐ mo 'o ί-

X XX

X XX <

</)

1 = X X X X OJ OJ OJ OJ OJ zri cn cn cn cn cn X X X X jz o o o o Oh 1 ¹ X X X X 1 o o o o o

cn cn, cn cn cn xx x xx ου o o o

CE and

X

Ό

O cn oj X X o o

X

X o o li m x o o OJ Oj X X o o

-157o

·; · • P · · ·

-P

n - «o n • »H o n —4 Oh n —4 Oh w —I υ β) —4 Oh M «Z4 Oh 01 —1 O o o o and o o o Oh Oh • • « • • • • • • 04 i. he ST o- o Ol 00 o zr Oh 04 he sr vO OJ ST he <43

I 0) And lilies

m O t ώ Ο ο o Oh o Oh • CI · • • * « • • • σ> σν he m 00 o vo he ον he a- and Ol • = r OJ . - ¹ - 4—

CM

X u

tl

X o

X m

x cj and m xx on 04 oj x cj cj cj x on x

X X o

I

X cj tl

X

CJ

I

X u

II X o

I

Table TV (continued)

OJ c

ΧΧΧΧΧΧΧΧ

OJ on

X cj x

CJ

OJ OJ OJ OJ Ol 04 04 04 z ·. z-x z> z ^ he he he he he he he he X X X X X X X X in Oh o o CJ CJ CJ CJ ^ z * ^ z X X sz X X X X X in cj in CJ CJ CJ CJ CJ

_ «Γ οηοηοησιοηοηοηοηοη - 'X ΧΧΧΧΧΧΧΧΧ axis I ο cjcjcjcjcjcjcjcjcjcj onj

ο ιη χ

νθ cj m he oj m he he he m he i ΧΧΧΧΧΧΧΧ cvj οουωωυοοο

-.-158- Example 3θ

Preparation of cis- and trans-methyl 2- (4-isopropyl-4-methyl-5-bioxo2-imidazolidinyl) nicotinate

<fH ₃

NH ₂ —CSNH ₂ CH (CH ₃ ) ₂

Using essentially the same conditions as described in Example 35, but using 2-amino-2,3-dimethylthiobutyramide instead of 2-amino-2,3-dimethylbutyramide, a mixture of cis- and transmethyl 2- (4-isopropyl-4- methyl-5-thioxo-2-imidazolidinyl) nicotinate from which a substantially pure trans-isomer, mp, 127-129 ° C, can be isolated by chromatography of the crude product on silica gel. T.t. the cis-isomer is 142-143.5.

Example 37

Preparation of cis- and trans-ethyl 2- (4-isopropyl-4-methyl-5-oxo-2imidazolidinyl-2-yl) quinoline-3-carboxylate

T

NH ₂ —CONH ₂ CH (CH ₃ ) ₂

Τ '

-159Using essentially the same procedure as described in Example 35 but using ethyl 2-formylquinoline-3-carboxylate [Godard et al., Buli, Chem. Soc. France, 906 (1971) 3 instead of methyl 2-formylnicotinate, cis-ethyl 2- (4-isopropyl-4 ~ methyl-5-oxo-2-imidazolin-2-yl) quinoline-3-carboxylate is obtained, m.p. 1-56 ° C and trans-methyl 2- (4-isopropyl-4-methyl-5-oxo + 2-imidazolin-2-yl) quinoline-3-carboxylate, m.p. Mp 163-164 ° C. Following the procedure of Example 33, but substituting substituted 2formylcarboxylate and using a suitably substituted aminoamide instead of 2-amino-2,3-dimethylbutyramide yields substituted 2- (2-imidazolidinyl) quinoline-5-carboxylate of formula IV.

Example 38

Preparation of dimethyl thieno [3,2-b] pyridine-5,6-dicarboxylate

NHCO ₂ Pri

DMAD

POCI3 / DMF ^S Υ ^ '^ Γ — CO ₂ CH ₃ -C0 ₂ CH3

A mixture of isopropyl-3-thiophenecarbamate (177 g; 0.975 mol) in 1.2 dm ^ methanol and 2.8 dm ^ water containing 200 g sodium hydroxide was heated to reflux for 4 h. The methanol was removed under reduced pressure and the cooled reaction mixture was extracted with 5 dm ether, the extracts were washed with water, aqueous NaCl solution and dried, Evaporation under reduced pressure gave 3aminothiophene as an oil in 57% yield of the crude material.

-1603-Aminothiophene was redissolved in methanol (500 ml) and cooled in an ice bath and 80 g or 0.50 mol of dimethylacetylenedicarboxylate was added dropwise, the mixture was stirred at room temperature for 15 h and 30 minutes; methanol was removed under reduced pressure and 1,2-dichloroethane was added. This solvent is also evaporated to give dimethyl 3-thienylaminobutendioate as an oil,

The Wilsmeier reagent was prepared dropwise, while stirring phosphorus oxychloride (86 g, 0.56 mol) in cooled (5%) DMF solution (41 g, 0.5θ mol) in 200 ml of 1,2-dichloroethane.

with .. * · · * ·

This reagent was stirred at room temperature for 1 hour and 40 minutes, diluted with 100 ml of 1,2-dichloroethane cooled to 5 ° C, and then the upper dimethyl ester dissolved in 400 ml of 1,2-dichloroethane was added to Vilsmeier by this reagent at 5% dropwise. for 25 minutes. The reaction temperature was raised to room temperature and maintained for 15 minutes, then refluxed for a further 4 h and 25 minutes. The cooled reaction mixture was chromatographed directly on a silica gel column to give 35.7 g (15%) of dimethyl thieno [3,2-b] pyridine-5,6 dicarboxylate, m.p. 124-125.5% after crystallization from hexanethyl acetate. Further yield (10.3 g) with m.p. 121-124% is obtained and so the total yield of isopropyl 3-thienocarbamate is 19%.

The above procedure and replacement of the appropriately substituted aminothiophene with isopropyl 3-aminothiophenecarbamate give the compounds illustrated below.

mp ^

CH ₃ 126-1 * ch ₃ ch ₃

-161Example $ 9

Preparation of dimethyl thieno [3,2-b3pyridine-5,6-dicarboxylate ^S V-CHO

C.

NHCOCH3

1. H2SO4

2. DMAD

3. POCI3 / OMF

o ₂ ch ₃

O ₂ CH3

To concentrated sulfuric acid (170 ml), while stirring at room temperature, 17.5 6 or 0.10 mol of 3-acetylamino-2-formylthiophene was added in batches. The mixture was heated to 50 ° C for 30 minutes, cooled and poured into ice-water. After neutralization with excess sodium acetate, the mixture was extracted with 1 χ 2 dm ^ ether. The organic layer was dried over anhydrous Na2SO4 and stripped to a dark red gum consisting of 3-amino-2-formylthiophene. Dimethylacetylenedicarboxylate (DMAD) (13 ml) in 5 ml of acetic acid, 5 ml of piperidine, 100 ml of methylene chloride and 100 ml of toluene are added 3-amino-2-formylthiophene and the mixture is stirred overnight, the methylene chloride is removed by distillation and then the mixture is heated to reflux for 24 h. After cooling and the addition of 13 ml of new DMAD, the reaction mixture was heated to reflux for 7 to 5 hours. After standing for 60 h at room temperature, the solvents were removed and the dimethyl thieno [3,3-b] pyridine 5,6-dicarboxylate product was obtained by chromatography, after elution with hexane-ethyl acetate and m.p. 124—125 ° 0.

Example 40

Preparation of dimethyl 3-chloro [3,2-b) pyridine-5,6-dicarboxylate and dimethyl 2,3-dichlorothieno [3,2-b] pyridine-5,6-dicarboxylate

A solution of dimethyl thieno [3,2-b] pyridine-5,6-dicarboxylate (15 g; 0.0525 mol) in 680 ml of acetic acid and sodium acetate and

(86 g; 0.093 mol) were maintained at 58 ° C while chlorine was slowly introduced

-162 for 5 and 45 minutes. After the reaction was complete, 200 ml of ethyl acetate were added to the mixture under a stream of nitrogen and the solid NaCl filtered and washed with ethyl acetate. The mother liquor is rinsed and fused and then the solvents are removed at reduced pressure. The residue is grown xX-cq ₂ CH ₃

C0 ₂ CH ₃

Cl ₂

precipitated in methylene chloride and the solution washed with water, extracted again with methylene chloride and the combined methylene chloride layers washed with aqueous sodium bicarbonate, dried and stripped to give 18 g of silica gel, chromatography on silica gel with 15% ethyl acetate-hexane, % ethyl acetate-hexane, gives the 2,3-dichloro compound, mp 173-178 ° C, 1.3 g, then the 3-chlorothio compound m.p. 166-173 ° C after crystallization from ethyl acetate-hexane.

Example 41

Preparation of dimethyl 3-bromothieno [3i2-b] pyridine-5,6-dicarboxylate

O ₂ CH ₃ CO ₂ CH ₃

No. ₂

A solution of bromine (20 g, 0.125 mol) in 5θ ml of acetic acid was added dropwise over 3 h to a solution of dimethyl thieno [3 »2-b] pyridine-5,6-dicarboxylate (26.3 g, 0.104 mol) contains 17,2 g or 0,2 mol of sodium acetate in 3θθ ml of acetic acid at 85 ° 0 »

-163 Add 18 g of sodium acetate and 20 g of bromine in 50 ml of acetic acid for 1 h and stir the mixture at 85 ° 0 overnight. 10 g of bromine are added in one batch and the temperature is maintained at 85 ° 0 for 4 h. The mixture was cooled and treated with aqueous sodium bisulfite solution, diluted with ethyl acetate and concentrated. The reaction product was partitioned between water and methylene chloride and the organic layer was washed with aqueous NaCl and the solvent removed. The residue was washed with ether to give 25 g of crude product in the form of needles from dimethyl 3-bromothieno [3,2-b] pyridine-5,6-dicarboxylate, t, t. 168-169 ° 0.

164-

Example 42

Preparation of thieno [3,2-b] pyridine-5,6-dicarboxylic acid

CO2CH3

N

NaOH

H ₂ 0 (f ^s

4 ~~ CO2H

Dimethyl thieno [3,2-b] pyridine-5,6-dicarboxylate (3.75 g »

Λ

0.0149 mol) was added to a solution of sodium hydroxide (1.8 g, or 0; 045 mol) in 20 ml of water and the mixture was heated to 60 ° C for 20 h. The reaction mixture was diluted with water, cooled in an ice bath, and acidified by the addition of concentrated hydrochloric acid, the precipitate of thieno [3,2-b] pyridine-5,6-dicarboxylic acid was filtered and dried overnight, yielding 3. 1 g (95%) t, t. over 380 ° C.

By the above procedure and the substitution of suitably substituted diesters of thieno [3,2-b] pyridine-5,6-dicarboxylic acids, the compounds illustrated below are obtained.

-165-

r ₉ - R 10 H H H Cl H Nr H I H F H CN H och ₃ H OH H N0 ₂ H N (CH ₃ ) ₂ ch ₃ H H ch ₃ ch ₃ ch ₃ H ocp.f ₂ H sch ₃ H are ₂ n (ch ₃ ) C6 «5 H « - (ch ₂ ) ₃ - Cl - (CH ₂ ) 4 - (CH) ₄ - Cl H C6 »5. C6H ₅ H H £) C ₆ H ₅ cf ₃ Έ

t «t. ° O> 380 not isolated> 380

-166Example 4-3

3-Chlorothieno [3,2-b] pyridine-5,6- iicarboxylic acid anhydride is obtained

3-ChlorothienoC3,2-b] pyridine-5,6-dicarboxylic acid (1.4-5 g) was heated at 85-90 ° C for 30 miflut then 90-102% for 30 minutes in 7 ml of anhydride acetic acid, the reaction mixture was cooled, the solids were filtered off and washed with ether to give 1.2 g of 3-chlorothieno [3,2-b] pyridine-5,6-dicarboxylic acid anhydride,

Using the above procedure and using the appropriate pyri din-5,6-dicarboxylic acid instead of 3-chlorothieno [3 »2-b] pyridine 5,6-dicarboxylic acids, the compounds illustrated below are obtained.

-167-

J9 ^R 10 H H H CI H Nr CI H CI CI H no ₂ ch ₃ H H N (CH ₃ ) ₂ H sch ₃ H och ₃ H ch ₃ H F H I ch ₃ ch ₃ H CN H OCHF ₂ C6 «5 H H SO ₂ N (CH ₃ - (ch ₂ ) ₃ - - (CH ₂ ) ₄ - - (CH) 4- CI CI H C6 ^r 5 ' C6 «5 H V H QC ₆ H ₅ cf ₃ H

> 2

mp ° C

266-267

Solids, not obtained m.p.

> 380

-168Example 44

5 - [(1-Carbamoyl-1,2-dimethylpropyl) -3-chlorothieno [3,2-b] pyridine-6-carboxylic acid is obtained

2-amino-2,3-dimethylbutyramide (0, 1g) in one batch was added to a stirring solution containing 1.2 g of 3-blortieno [3,2-b] pyridine-5,6-dicarboxylic acid anhydride in 1 ml THP. After standing for 5 minutes, the ice bath was removed and the reaction mixture was stirred at room temperature for 28 h. 5 ml of THP was added and the mixture was heated to reflux for 2 h and then set aside overnight. The cooled mixture was filtered and the collected solid was washed with ether to give 1.4 g of the desired 5 - [(1-carbamoyl-1,2,2-dimethylpropyl) -3-blortieno [3,2-b] pyridine-6-carbon acid.

Using the above procedure and using suitable pyridine-5,6-dicarboxylic acid · anhydride instead of 3-chlorothieno [3,2-b] pyridine-5,6-dicarboxylic acid anhydride and a suitable aminoamide, the following compounds are obtained.

-169-

R? - <% - ci> 2H r _x RlO— N —CONH— <p— ^R 2 RiO * 1 «2 H H ch ₃ iC ₃ H ₇ H Cl ch ₃ j.-C ₃ H ₇ Cl H ch ₃ iC ₃ H? Cl Cl ch ₃ ic ₃ H ₇ H Nr ch ₃ iC ₃ H ₇ H Me ch ₃ iC ₃ H ₇ H NO ₂ ch ₃ A-C3H7 H N (CH ₃ ) ₂ ch ₃ i.-C ₃ H ₇ H sch ₃ ch ₃ 1-C3H7 H och ₃ ch ₃ ic ₃ h ₇ ch ₃ H ch ₃ iC ₃ H ₇ H sch ₃ ch ₃ iC ₃ H ₇ H H ch ₃ c ₃ h ₇ H H ch ₃ c ₂ h ₃ H ochf ₂ ch ₃ iC ₃ H ₇ ch ₃ ch ₃ ch ₃ iC ₃ H ₇ H CN ch ₃ iC ₃ H ₇ H F ch ₃ 2-C3H7 H J CHq iC ₃ H ₇ H are ₂ n (ch ₃ ) ₂ ch ₃ iC ₃ H ₇ ^C 6 ^H 5 H ch ₃ iC ₃ H ₇ - (ch ₂ ) ₃ - ch ₃ iC ₃ H ₇ - (ch ₂ ) ₄ - ch ₃ iC ₃ H ₇ - (ch) ₄ - ch ₃ iC ₃ H ₇ H C6 «5 CH: iC ₃ H ₇ C6H5 H ch ₃ iC ₃ H ₇ H oc ₆ h ₅ CH: iC ₃ H ₇ cf ₃ H ch ₃ i ' ^c 3 ^H 7

impure

mp ° c

-170Example 45

Purification of 5- (4 ~ isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl) thieno [3,2-b] pyridine-6-carboxylic acid

1 1 ΥΥγ - CO ₂ H Ac ₂ O n L.AC02H 1 <z

N <pH ₃

NH ₂ - (j: —C0NH2 CH (CH ₃ ) ₂ ^S Ύ> - <° 2Η <-h ₃

CONH— (j) —C0NH2

CH (CH ₃ ) ₂

1. NaOH

2. H +

Thieno [3,2-b] pyridine-5,6-dicarboxylic acid (2.5 g or 0.011 mol) was gently heated to 85 ° C for 1 hour with 25 ml of acetic anhydride, then cooled, filtered and washed with diethyl ether to give a solid anhydride, m.p. 266-267 ° C. A mixture of anhydride and 2-amino-2,3 - dimethylbutyramide (2 "6 g or 0.02 mol) in 70 ml of THP was stirred at room temperature for 15 h. After tefluxing for 2 h, the mixture was cooled and diluted with 50 ml THP. Solid 5 - [(1-carbamoyl-1,2-dimethylpropyl) carbamoyl) thieno [3 »2-b] pyridine-6-carboxylic acid is filtered, washed with ether and dried. The same is mixed with 60 ml of aqueous NaOH solution (6 g, 0 ', 05 mol).

-171i is heated to 85 ° C for 2 hours and 30 minutes, then set aside at room temperature. After cooling in an ice bath, the mixture was acidified to pH 3 with concentrated HCl. The solid (3 g) was filtered and dried. Crystallization from ethyl acetate gave pyl-4-methyl-5-oxo-2-imidazolin-2-yl) thieno [3,2-b] pyridine-6-carboxylic acid, t. 242-244 ° C in 46% yield.

Using the above procedure and substituting the appropriate ^ pyridine 5 »6-dicarboxylic acid instead of thieno [3i2-b] pyridine-5» 6-dicarboxylic acid, the compounds illustrated below are obtained.

- ^R io t »t. ° CHH 242-244 H Cl 238-239

Suppression of diethyl furo [5,2-b] pyridine-5,6-dicarboxylate

HO

NH ₂

02 ^c 2 ^h 5

O ₂ C ₂ H5

-1723-amino-2-formylfuran, obtained from 3-azido-2-formylfuran (8.9 g, 0.065 mol) is dissolved in ethanol and diethyl oxalacetate (12.23 g, 0.065 mol) and ten drops are added to this solution. piperidine, A dusted 5A ° molecular sieve was added and the reaction mixture was stirred at 65-60 ° C for 3 h, then 2.2 g of diethyl oxalacetate were added. The reaction was essentially complete after 12 h at 55-6θ ° θ · After cooling, the reaction mixture was filtered, and the filtrate was concentrated and then dissolved in ethyl acetate, washed with water, then brine, dried over anhydrous magnesium sulfate and evaporated to dryness. is dissolved in 3: 1 hexane: ethyl acetate and passed through a two phase chromatographic column. The first vacuum is filtered through a 10-13 cm silica layer from which at least three fractions containing the required product are collected and combined. These combined fractions were then passed through a 15 cm column and eluted under pressure with ethyl acetate: hexane 3: 1 and 2: 1. Crystallization from hexane-ether gives 4.15 g or 24% diethyl furo [3,2-b] pyridine 5,6-dicarboxylate, m.p. 60-64 ° C, and with a mass spectrum of m / e 264,

The above procedure and using the suitable furan instead of 3-amin-2formylfuran give the compounds below

Rg ^R 10 R ” mp ° c H H c ₂ h ₅ 60-64 H Cl c ₂ h ₅ ch ₃ H - c ₂ h ₅ H • ch ₃ c ₂ h ₅ c ₂ h ₅ H c ₂ h ₅ H c ₂ h ₅ c ₂ h ₅ ch ₃ ch ₃ c ₂ h ₅

I

-173Jrimgr 47

Purification of furo [3,2-b] pyridine-5,6-dicarboxylic acid

γ ^Ζχ \ - € 0 ₂ θ2Η ₅ Ί 1 1 co ₂ h —V <2 — C0 ₂ C ₂ H5 N φ — C0 ₂ H N Furo [3 »2-b] pyridine-5» 6-dicarboxylic acid, diethyl ester

(1.1 g, 0.0042 mol) was dissolved in 95% ethanol (20 ml) containing 20 ml of 10% aqueous sodium hydroxide and set aside at 0 ° for 2 days, the mixture was cooled, acidified and the solvent removed. under reduced pressure. 5 ml of water is added and the hydrated product of the diacid is obtained as a brown solid by filtration,

3.31 g (99%), mp, 183 ° C (dec). Analysis for C 24 H ₂₉ NO 2 .21 / 2 H ₂ 0: Calculated: 0 42.86; H 3 29; N 5 »55.

Found: C, 42.63; H, 2.63; N 5 »46.

Example 48

Preparation of furo [3,2-b] -pyridine-5,6-dicarboxylic acid anhydride

Puro [3 »2-b] pyridine-5,6-dicarboxylic acid (3.3 g or O» O159 mol) in 100 ml of acetic anhydride was heated to 7θ-80 ° 0 for 6 h. The reaction mixture was cooled, filtered and the solid was washed with ether to give 3 »01 (100%) crude furo [3» 2-b] pyridine-5 »6-dicarboxylic acid anhydride.

-174Example 4-9

Preparation of 5 - [(1-carbamoyl-1,2-dimethylpropyl) -carbamoyl3furoC3,2-benzyridine-6-carboxylic acid and 5- (4-isopropyl-4-methyl5-oxo-2-imidazolin-2-yl) furo [ J, 2-b3pyridine-6-carboxylic acids

<pH (CH ₃ ) ₂ H ₂ N —— conh ₂ ch ₃

CH ₃

CONH-C-CONH ₂ N |

CH (CH ₃ ) ₂

1. NaOH

2. Acid

-175 Furo [3,2-b] pyridine-5-6-dicarboxylic anhydride (3.01 g or 0.015 mol) was suspended in 100 ml of THF and 2-amino-2,3-dimethylbutyramide (2.3 g or 0.018 mol) was added ). After stirring for 20 h, the solution was evaporated to an oily solid which dissolved in water / dilute NaOH solution. The alkaline solution is extracted with methylene chloride and then acidified and re-extracted with methylene chloride when traces of material are isolated after only one minute of mixing. The aqueous layer was concentrated to an oily solid, which was dissolved in ethanol and filtered, re-concentrated to a purple gum that mainly contained the crude product, 5 - [(lcarbamoyl-1,2-dimethylpropyl) carbamoyl] furo [3 »2-b] pyridine-6-carboxylic acid used without further purification to obtain the final 2-inidazolin-2-yl) product by dissolving it in 10% NaOH solution (40 acre) and heating at 80 ° C for 3 h. After cooling, the reaction mixture was acidified and a small amount of solid filtered off. Concentrating the raatic lye yields a second yield, which is collected and combined with the first yield. Purification is done by taking half of the material and separating on silica gel preparatively on glass plates. From a weak lane using methylene chloride: ethyl acetate: chloroform: methanol 1: 1: 1: 1 as the eluent to give the desired product, 2-imidazolin-2-yl product, m.p. 214-223 ° C (dec.). Esters then

Λ can be obtained by following the procedures described in Example 20.

-176 Using the above procedure and substituting the corresponding furo [3,2-b] pyridine-5,6-dicarboxylic acid anhydride, the compounds illustrated below are obtained.

CH ₃

R? —CO2H l l

RlO— ¹ - N- H r ₉ Rio H H H Cl CH ₃ H H ch ₃ c ₂ h ₅ H H c ₂ h ₅ ch ₃ ch ₃ Example 50

: h (ch ₃ ) ₂

1 = 0

mp ° c

214-223

Preparation of dimethyl thieno [2i3-b] pyridine-5,6-dicarboxylate n / a

SN ° 2 ^ch 3 DMF Γ ^ “| Γ ^ θ ² ^ ³ ° 2 ^ch 3 ^P ° ^Cl3 V— <02CH ₃ ^{with J} SN

H

The Wilsmeier reagent was prepared by adding dropwise, stirring, phosphorus oxychloride (40.29 g or 0.26 mol) to a cooled (10 ° C) solution of DMP (19 ^ 0 g, 0.26 mol) in 40 ml of 1,2-dichloroethane under nitrogen atmosphere. This reagent was stirred at room temperature for 1 hour and 45 minutes. Dimethyl-2-thienyl-aminobutenedioate (63i4 g or 0.26 mol dissolved in 300 ml of 1,2-dichloroethane) was added dropwise to Wilsmeier reagent at 7-10 ° C. The reaction temperature was raised to room temperature and maintained for 15 minutes, then to reflux for 12 h. The cooled reaction mixture was concentrated and the residue chromatographed at

-177columns with ethyl acetate-hexane gel to give dimethyl-thieno [2,3-b] pyridine-5,6-dicarboxylate (29 g, 4-5%) as a solid.

Using the above procedure and substituting dimethyl-2-thienylaminobutendioate, the compounds illustrated below are obtained, ^{R 1} 'T - f;

: o ₂ ch ₃

^R i <r- \ Λ 4 S N ? 10 ch ₃ H H H H ch ₃ ch ₃ ch ₃ H CfiH5 C6 «5 H cf ₃ H

80-82 solid Example 51

Preparation of dimethyl 3-bromothieno [2,3-b] pyridine-5,6-dicarboxylate

No. ₂

HOAc $ N NaOAc

Bromine (0.33 g, 0.00206 mol) in 8 ml of acetic acid was added to a stirring solution containing dimethylthieno [2,3-b] pyridine 5,6-dicarboxylate (0.5 g, 0.00187 mol) in acetic acid containing sodium acetate (0.31 g, 0.00377 mol) at 4 ° C. The reaction mixture was heated to 75 ° C for 18 h. Analyzing the mixture using tlc (thin layer chromatography) on silica gel indicated that the reaction was not complete. Another 0.33 g of bromine in acetic acid and sodium acetate (0.31 g) was added and heated at 75 ° θ for further

-1786 h. The reaction mixture was diluted with water and extracted into ethyl acetate. The separated organic layer was dried over anhydrous MgSO 4, filtered and the filtrate concentrated to an oil which solidified by standing. Crystallization of the crude product from ethyl acetate-hexane affords dimethyl 3-bromothieno [2,3-b] pyridine-5,6-dicarboxylate in needle form, m.p. 868 ° C, 5 ° C.

This compound can be easily converted to the various substituted-thieno [2,3-b] pyridine compounds as illustrated below, while electrophilic substitutions such as nitration or halogenation give the additional compounds listed below.

ri

-179-

Α —CO2CH3

Ν

r ₉ ^R 10 Η H Η Ci Η • Nr Η J Η F Η CN Η sch ₃ Η och ₃ Η n (ch ₃ ) ₂ Η ochf ₂ Η no ₂ Η CHO Η CH ₂ C1 ch ₃ H Η ch ₃ C1 H C1 Cl ch ₃ ch ₃ Η are ₂ n (ch ₃ ) ₂ -CCH ₂ ) 4- - (CH) and | - C6 «5 - (ch ₂ ) ₃ - H Η C6H5 Η oc ₆ h ₅ cf ₃ H

104-110

86-87.5

80-82

84-89

-180Example 52

Thieno [2,3-b] pyridine-5,6-dicarboxylic acid is obtained

II k A —co ₂ ch ₃

KOH

, 0 ₂ H> lk A Λ-cozH

- A solution containing dimethyl thieno [2,3-b] pyridine-5,6-dicarboxylate (27.75 g, 0.11 mol) and potassium hydroxide (30.98 g or 0.55 mol) in 200 ml of methanol in the nitrogen atmosphere was heated to reflux for 2 h. The reaction mixture was cooled and enough water was added to dissolve the solids present before evaporating the mixture to dryness. The resulting solid was dissolved in a minimum volume of water, cooled in an ice bath and acidified with concentrated H 2 SO 4 to a pH of about 1. Thieno [2,3-b] pyridine-5,6-dicarboxylic acid was filtered and dried overnight and thus obtained 23.36 g, mp Mp 272-275 ° C.

By employing the above procedure and substituting the pyridine-5,6-dicarboxylate used above by suitably substituted dialkyl [2,3-b] pyridine-5,6-dicarboxylate, the compounds illustrated below are obtained.

-181-

R _r with A —co ₂ h

S N

H

H

H

H

H

H

H

H

H

H

H

H

H

H cu ₃

Cl

Cl

CH3

C6 «5

H

- (CH ₂ ) ₃ - (CH ₂ ) 4- (CH) 4H

H cf ₃ ^R 10

H

Cl

Nr

J

F

CN sch ₃ och ₃

N (CH ₃ ) ₂

OCHF ₂ no ₂

CHO

CH ₂ C1 ch ₃

H

H

Cl ch ₃

H

S0 ₂ N (CH ₃ ) ₂

OC6H ₅

C6H5

H

272-275> 300. > 315

180-183 (raz,)

-182 «

Acetic anhydride ($ 7.4 g, 0.366 mol) was added to a stirring suspension containing thieno [2,3-b] pyridine-5,6-dicarboxylic acid (21.52 g or 0.096 mol) in 175 dimethoxyethane (DME ) in an inert atmosphere with nitrogen. After pyridine (16.78 g or 0.21 mol) was added at room temperature, an exothermic reaction of up to 45 ° C was observed and a homogeneous solution was obtained. The reaction mixture was then stirred at room temperature and the resulting solid filtered off, washed with ether and dried in air to give 14.8 g (75%) of thieno [2,3-b] pyridine-5,6-dicarboxylic anhydride .

Using the above procedure and using suitably substituted thieno [2,3-b] oridine-5,6-dicarboxylic acid, the compounds below are illustrated.

«J

-183-

ch ₃

H

H

H

H

H

H

H

H

H

H

H

H

H

CH3

C1

C1 ch ₃

C6 «5

H ^r 1Q

H 176-180

No. 228.5-231

C1 230-300 (bad grade) H

H

H cf ₃ žT

F

CN sch ₃

N (CH ₃ ) ₂

NO 2

CHO

CH ₂ C1 ch ₃

H

H

C1 ch ₃

H.

S0 ₂ N (CH ₂ ) ₂

- <ch ₂ ) ₃ - <CH ₂ ) 4- (CH) ijC6 «5 oc ₆ h ₅

H

-184Example 54

Purification of 6 - [(1-carbamoyl-1,2-dimethylpropyl) carbamoyl] thieno [2,5-hl pyridine-5-carboxylic acid

<f ^H S

CONH 2 CH (CH ₃ ) 2 <A-co ₂ h ch ₃ ^ 1 — CONH — CONH ₂ CH (CH ₃ ) ₂

2, amino-2,3-dimethylbutyramide (9.84 g or 0.076 mol) was added to a stirring suspension containing thieno [2,3-b] pyridine-5,6-dicarboxylic acid as anhydride (14.8 g or 0.072 mol) in THP under an inert atmosphere with nitrogen at a nozzle j temperature. The dark colored solution was stirred at room temperature overnight and obtained a solid solid, the material was filtered off, washed with THP and air dried to give 17.35 g (72%) of 6 - [(1-carbamoyl-1, 2- dimethylpropyl), carbamoyl) thieno [2,3-b] pyridine-5-carboxylic acid.

Using the above procedure and using suitably substituted thieno [2,3-b] pyridine-5,6-dicarboxylic acid as anhydride, the compounds below are illustrated.

-185 ^R 10 "

R _r conh— (j: —conh ₂ CH (CH ₃ ) ₂

Rg_

CH3

H

H

H

H

H

H

H

H

H

H

H

H

H

C'l

CI

CH3

C6 «5

H

- (CH ₂ ) ₃ - (CH ₂ ) ₄ -, (CH) ₄ H

H

CF3 ^R 10

H

Nr

CI

H

J

F

CN

SCH3

OCH3

N (CH ₃ ) _{2 to 2}

CHO

CH ₂ C1

CH3

H

CI

CH3

H

SO ₂ N (CH ₃ ) ₂

207-208

176-178

156-158

C6 «5

OC ₆ H ₅

H

-186Example 55

6- (4-Isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl) thieno [2,3-b] pyridine-5-carboxylic acid

° 2 ^H <pH ₃

ONH— (j: —C0NH ₂ CH (CH ₃ ) ₂

C0 ₂ H

NCH ₃

--CH (CH ₃ ) ₂

- = 0

6 - [(1-Carbamoyl-1,2-dimethylpropyl) carbamoyl] thieno [2,3-M pyridine-5-carboxylic acid (17.35 g ίϋ 0.052 mol) was added to 225 ml of water containing sodium hydroxide (10 , 35 g or 0.26 mol). The resulting alkaline solution was heated to 80 ° C for 2 hours and cooled in ice-water bath for 4-5 minutes and acidified with 6M H 2 SO 4, Product 6- (4-isopropyl-4-methyl-5-oxo-2 -imidazolin-2-yl) thieno [2,3-b] pyridine-5-carboxylic acid is filtered off, washed with water and dried in a spirit, yielding 1.54 g, 70.3%, m.p. 221-223% v

-187Example 5θ

Preparation of 2-isopropyl-2-methyl-5H ^, - ^ ^m: id- ^azo [I ^> .2? il, 2] pyrrolo [3 4 ~ b] thieno [5,2-e] pyridin-3 (2H), 5-dione

Dicyclohexylcarbodiimide (1) 07 S or 0.005 mol) in 20 ml of methylene chloride was added dropwise to a stirring suspension containing JO ml of methylene chloride, 6- (4-isopropyl-4-methyl-5-oxo-2imidazolin-2-yl ) thieno [2,3-b] -5-carboxylic acid (1.5 g) 0.0047 mol) under a nitrogen atmosphere. After stirring the reaction mixture for 16 h, it was carefully treated to give a clear, concentrated to dryness and the resulting material purified by silica gel column chromatography eluting with acetonitrile / methylene chloride (1/2). the product crystallizes from toluene to give pure J, J dione in the form of white crystals, mp 214,5216,5.

-188Example 57

Preparation of 2-propynyl 6- (4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl) thienoC2,3-b] pyridine-5-carboxylate

NoH

H0H ₂ CC = CH

C0 ₂ CH ₂ CeCH

F = 0

CH (CH ₃ ) ₂

Sodium hydride (2.4 g, 60%, 0.126 mol) was added to 3,5-dione (0.9 6 or 0.003 mol) in 25 ml of propargyl alcohol at 10 ° G under an inert atmosphere with nitrogen. The reaction mixture was stirred. at room temperature for 60 h then neutralized with saturated ammonium chloride solution. The resulting mixture was concentrated on a rotary evaporator, diluted with water and extracted with ethyl acetate. The organic layer was separated by drying over anhydrous MgSO4 and concentrated to dryness.

Purification of the product by silica gel column chromatography with methylene chloride / acetonitrile (85/15) affords 2-propynyl 6- (4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl) pyridine-5-carboxylate , which after crystallization from toluene has a mp 188-189s5 ° θ

-189 Using the methods of Examples 49, 55, 56 and 57 and using suitably substituted thieno or furo [3,2-b] pyridine or thieno or furo [2,3-b] pyridine compounds, the compounds below are illustrated

B R9 frio R t ° t. ° C S H H CH3 215-217 S H H H 220-223.5 (raz.) Š H H -CH ₂ CeCH 188-189.5 S H H 0 ch ₃ 140-142 S H H -ch ₂ c-ch ₂ 108-110 S 'ch ₃ H H 225.5-227.5 S H Nr H 274-276 s H ci H 266-267 0 H H H 237-244 s H no ₂ -ch ₃ 201-202.5 ° C s H no ₂ . H 260 (ra &.) s Cl H H 268 (r »e.) s H CH3 H 255-257 s - (CH2) 4- H 234-237 0 H Cl H 239-240

-190-

B R9 Rio R 0 H H CH3 134-137 0 H Nr H 239-245 0 CH3 H H 174-177 0 c ₂ h ₅ H H 170-172 0 C6 «5 H H 244-245 0 H Cl CH3 137-141 0 H H ch ₂ - 1 1 \ / 0 137-141 0 H H CH ₂ C ₅ CH 150-156 1 1 A pCO ₂ R M.. CH (CH ₃ ) ₂ PH- » k 4 N which - Λ.Π3 ^K 10 '- H <= - u B Rio R9 R S H H H 242-244 S H Cl H 238-239 S H Nr H 226-227 S H H -ch ₂ - 1 1 \ Z 0 156-157 0 H H «J H 214-223 s Cl H H 266-267

-191Example 5B L / ⁷

Deactivation of methyl 5- (4-isopropyl-4-methyl-5-oxo-2-imidazolidinyl · furo [3,2-b] pyridine-6-carboxylate ⁰ V ^^ s-COOCH

I 'I

NH: h (ch ₃ ) ₂ p: H ₃

J = o

NaCNBH ₃

A solution of 22.1 mmol methyl 5- ( ^z 4- ^z 0propyl-4-methyl-5-oxo2-imidazolin-2-yl) furo [3,2-b] pyridine-6-carboxylate in methanol was cooled to 0 ° C and a few drops of methyl orange indicator are added. The solution was stirred and treated with 22.1 mol of concentrated HCl. The solution was then treated with 22.1 moles of sodium cyanoborohydride, and the pH was maintained at about 3 by the addition of 2M methanolic HCl, stirred overnight, cooled to 0 ° C and the pH of the solution to about 0 With HCl to decompose the residual NaONBH 2. The pH was then adjusted to 5-θ with 5M NaOH, the methanol removed in vacuo and water added to dissolve the inorganic salts. The mixture was extracted with and the extracts were dried and concentrated to give the title compound.

Using the above procedure with suitably substituted 2 (2-ylidazolin-2-yl) furo [3,2-b] pyridine-6-carboxylate, the corresponding 2- (2-imidazolidinyl) furo [3,2-b] pyridine-6 is obtained -carboxylate Similarly, the reaction of a suitably substituted methyl 2- (2-imidazolin2-yl) thieno [3,2-b] pyridine-6-carboxylate gives the corresponding methyl 2- (2-imidazolinyl) thieno [3 »2-b] pyridine- 6-carboxylate. The reaction products are illustrated below:

Similarly, by applying the above procedure with suitably substituted methyl 2- (2-imidazolin-2-yl) dihydro- or dihydrothieno [3 »2-b] pyridine-6-carboxylate to give appropriately substituted methyl 2K (2-imidazolidinyl) dihydro- or dihydrothienoC3. 2-b] pyridine-6-carboxylate. The reaction products are given below:

193 '

B , W ^R 9 ^R 10 "· - - 0 - 0 H H s s H H s 0 H H 0 s H H 0 0 H Cl s s H Cl s 0 H Cl 0 s H Cl 0 0 ch ₃ H s s ch ₃ H s 0 ch ₃ H 0 s ch ₃ H 0 0 H ch ₃ s s H ch ₃ s 0 H ch ₃ 0 s H ch ₃ 0 0 c ₂ h ₅ H s s c ₂ h ₅ H s 0 c ₂ h ₅ H 0 ' s ^c 2 ^h 5 H 0 0 H c ₂ h ₅ s s H c ₂ h ₅ s 0 H c ₂ h ₅ 0 s H c ₂ h ₅ 0 0 . ^CH 3 ch ₃ s s ^ch 3 ch ₃ s 0 ch ₃ ch ₃ 0 s ch ₃ ch ₃ 0 0 H Nr s s H Nr s 0 H Nr 0 s H Nr

-194Example 59 t /

Preparation of cis- and trans-methyl 6- (4-isopropyl-4-methyl-5-oxo-2-imidazolidinyl) thieno [2,3-b] pyridine-5-carboxylate

NoCNBH ₃

H (CH ₃ ) ₂ .

/ \ - C00CH '

CH (CH ₃ ) ₂

Using essentially the same process as described in Example 5S but using 6- (4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl) thieno [2,3-b] pyridine-5-carboxylate instead 5- (4isopropyl-4-methyl-5-oxo) -2-imidazolin-2-yl) furo [3,2-b] pyridine6-carboxylate give two products of cis-methyl 6- (4-isopropyl4-methyl-5 -oxo-2-imidazolidinyl) thieno [3,2-b] pyridine-5-carboxylate tt 185-186 ° C and trans-methyl 6- (4-isopropyl-4-methyl-5-oxo-2-imidazolidinyl) thieno [2,3-b] pyridine-5-carboxylate, m.p. 145-148 ° C.

-195Applying the above procedure with suitably substituted methyl thieno-, dihydrothieno-, furo- or dihydrofuro [2,3-b] pyridine-5-carboxylate, the sft reaction products are further illustrated.

^R 10 "

R? Rl2 ^R ll / ^ V-COOCHz \ d BN

HN

H CH _{3 N} VJ

H (CH ₃ ) ₂ fc = W / ^ V-COOCH-

HN

H CH ₃ N ^{Y 4}

H (CH ₃ ) ₂ so / 'V-COOCH = W

N

HN3 <? H ₃ : h (ch ₃ ) ₂ gets t = 0 r ^/ 6v-coocH ₃ nY ³

HNt.t. 170 - 174 ° C 'CH (CH ₃ ) ₂

Ό

-196Example 60

Preparation of trans-6- (4-isopropyl-4-methyl-5-oxo-2-imidazolidinyl) thieno [2,3-b] pyridine-5-carboxylic acid - COOCH · »

S N

HN

Kf ³

CH (CH ₃ ) ₂

NaOH

By applying essentially the conditions set forth in Example 32, but using trans-methyl 6- (4-isopropyl-4-methyl-5-oxo-2-imidazolidinyl) thieno [2,3-b] pyridine-5-carboxylate instead of cis- methyl 6-allyloxy) -2- (4-isopropyl-4-methyl-5-oxo-2-imidazolidinyl) nicotinate to give the product trans-6- (4-isopropyl-4-methyl-5-oxo-2imidazolidinyl) thieno [ 2,3-b] pyridine-5-carboxylic acid, mp 225-226 ° C in the form of sesquihydrates.

v »

-197 Similarly, the furan analog provides the corresponding imidazolidinones listed below.

COOH

HNH CH3 'and' CH (CH ₃ ) ₂ = 0

m.p. 210-218 ° C / '' S-COOH

HN

H CH3 N \ T ^J 'I' CH (CH ₃ ) ₂ = 0

m.p. 176-178 ° C

-198Example 61

Preparation of diethyl 5-acetyl-1,6 dihydro-6-oxo-2,3-pyridinecarboxylate

f) c — nh ₂ <j> c ₂ H ₅ <j: ooc ₂ H ₅ 0 = C —— c = o ch-oc ₂ h ₅

Sodium acetate

CH3 —C

Sodium acetate (30 g or 0.37 mol) was added to a stirring mixture containing diethyl (ethoxymethylene) oxalacetate (87 g, 0.36 mol) and acetoacetamide (36 g, 0.36 mol) in 300 ml absolute ethanol .

After stirring the reaction mixture for 30 minutes, the ethanol was distilled off under reduced pressure, the residue acidified to pH 2 with dilute aqueous hydrochloric acid and the resulting solid separated by sieving. Crystallization from the ethanol / water mixture afforded diethyl 5-s ^L cetyl-1,6-dihydro-6-oxo-2,3-pyridinedicarboxylate in the form of crystals, mp 200-209 ° C.

-199Example 62

Preparation of diethyl 5- (bromoacetyl) -1,6-dihydro-6-oxo-2,3-plridindicarboxylate

Bromine (8.0 g, 0.050 mol) in 48% HBr was added dropwise to a stirring solution containing diethyl 5-fi ^L cebyl-1-6-dihydro-6-oxo-2,3-pyridinecarboxylate (14.05 g. 0.05 mol in 200 ml of 48% HBr After the reaction was complete, the reaction mixture was poured over 200 g of ice and the mixture was stirred until the ice had melted. The crude product was collected by filtration and crystallized twice from ethyl acetate bexane ( 1/2) to give diethyl 5- (bromoacetyl) -1,6-dihydro-6-oxo-2,3-pyridinedicarboxylate, mp 141-142 ° C.

Example 63

Preparation of diethyl 5- (2-bromo-1-hydroxyethyl) -1,6-dihydro-6-oxo2,3-pyridinedicarboxylate and diethyl 2,3-dihydro-3-bidroxy-furo [2,3-b] pyridine-5 , 6-dicarboxylate

Sodium borohydride (2.54 g or 0.066 mol) was added in batches over 30 minutes to a stirring suspension containing diethyl 5- (bromoacetyl) -1,6-dihydro-6-oxo-2,3-pyridinedicarboxylate (57 (2 g, 0.159 mol) at 10-20 ° C. After the addition of sodium borohydride is complete, the reaction mixture is stirred maintaining the room temperature. 100 g of ice are stirred and the mixture is stirred until the ice is melted. The mixture was then concentrated in vacuo and the residue was recrystallized twice from ethyl acetate-hexane to give pure diethyl 5- (2-bromo-1-hydroxyethyl) -1,6-dihydro-6-oxo-2,3-pyridine- 200dicarboxylate, mp 134-138 ° C.

NaBH ₄ £ -03)) 7 OH (C 2 H 5) ₃ N

OHco 2C2H5 \ G ° 2 ^c 2 ^h 5

O N

Mixing this compound with triethylamine (1.0 ml / g solid) in methylene chloride for 1 h, then washing the organic growth of the residue with dilute HCl, water, brine and drying over anhydrous MgSO4 to give a crude furo [2. 3-b] pyridine as an oil after removal of the solvent in vacuo. Crystallization from the cyclohexane-toluene mixture afforded pure diethyl 2,3-dihydro-3-hydroxy-furo [2, '3-b] pyridine-5,6-dicarboxylate, m.p. 73-77 ° C.

Example 64

Preparation of diethyl furo [2,3-b] pyridine-5,6-dicarboxylate

N θ2 ^ 2 ^ 5 £ - · froluenesulfonic acid

Δ xylene

CO ₂ C ₂ H ₅ <Λ ~ € 0 ₂ Ο ₂ Η ₅

N

A solution in xylene of the hydro-furo compound obtained in Example 61, (3.7 g) containing para-toluenesulfonic acid in an amount of 0.01 g is heated to reflux for 2 h, the solution is cooled and the xylene solution is decanted. The residue was extracted with ether and the extracts were combined with xylene. Distillation of the solvent gave a solid yellow solid crystallized from ames cyclohexane-toluene to give pure diethyl furo [2,3-h] pyridine-5,6-dicarboxylate, mp 66-77 ° C.

Example 65

Preparation of furo [2,3-b] pyridine-5 »6-dicarboxylic acid

° 2 ^ 2 ^H 5

KOH

0 ₂ H o ₂ h

Potassium hydroxide (5 »60 S, 85%, 0.087 mol) in 5 ml of water was added to a stirred suspension of diethyl furo [2,3-b] pyridine-5» 6-dicarboxylate (9.3 g, 0.035 mol) in 100 ml of absolute ethanol. The reaction mixture was heated at 60 ° C for 1 h, then cooled and anhydrous acetone added, the precipitate was filtered off, dried, suspended in dry acetone and treated with hydrogen chloride to adjust the pH to 2, Crystallization of the isolated solid from ethyl acetate-acetone gives furo [2,3-b] pyridine-5,6-dicarboxylic acid, m.p. 189-192 ° 0.

Example 66

Preparation of Furo [2,3-b] Pyridine-5,6-dicarboxylic acid as anhydride

Puro [2,3-b] pyridine-5,6-dicarboxylic acid (6.7 g, 0.032 mol) was heated at 60 ° C for 30 minutes in 150 ml of acetic anhydride, the reaction mixture was cooled to room temperature and concentrated in vacuum, and the residue is triturated with cyclohexane-ether (5: 1) »

-202 is filtered and dried to give 5.35 S furo [2,3-b] pyridine-5i, 6-di-

Example 67

Purification of 6 - [(1-carbamoyl-1,2-dimethylpropyl) carbamoyl) -furo [2,3-b] pyridine-5-carboxylic acid

2-amino-2,3-dimethylbutyramide (2.1 g, 0.016 mol) was added to the stirring suspension and consisted of 3.0 g or 0.016 mol of furo [2,3-b] pyridine-5,6- of dicarboxylic acid as anhydride in 7.5 ml of tetrahydrofuran, and the mixture was allowed to stir at room temperature.

for 16 h, then stirred at 60 ° for 1 h, cooled to room temperature and dried, yielding 5 g of 6 - [(1-carbamoyl-1,2-dimethyl or propyl) carbamoyl] furo [2. 3-b] pyridine-5-carboxylic acid, mp 192-196.

-203Example 68

Preparation of 6- (4-propyl-4-methyl-5-oxo-2-imidazolin-2-yl) furo [2,3-b] pyridine-5-carboxylic acid

h ₂ o

NaOH ° 2 ^h <pH ₃ ONH-C-CONH ₂ CH (CH ₃ ) ₂

A solution containing 6 - [(1-carbamoyl-1,2-dimethylpropyl) carbamoyl] furo [2,3-b] pyridine-5-carboxylic acid (3.8 g or 0.012 mol) in aqueous NaOH (2.4 g or 0.06 mol) in 40 ml of water was stirred at 65 ° C for 3 b. The reaction mixture was then warmed to 75 ° C for 1 h, allowed to cool, poured onto ice, acidified to pH 2-3 and the resulting solid filtered off and dried. Crystallization from the acetone-methanol mixture afforded pure 6- (4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl) furo [2,3-b] pyridine-5-carboxylic acid, m.p. 237-244 ° C.

Example 69

Preparation of 2,3-dihydro-6- (4-isopropyl-4-methyl-5-oxo-2-imidazoline

2-yl) furo [2,3-b] pyridine-5-carboxylic acids

-204 Solution of 6- (4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl) furo [2,3-b] pyridine-5-carboxylic acid (1.7 g or 0.056 mol) and 1 , 0 g (0.0072 mol) of potassium carbonate in 200 ml of 9: 1 ethanol: water is added to 100 mg of 5% palladium on coal as a catalyst in a 500 ml balloon for pressure work. The bottle is connected to a Parr hydropower plant and pressurized with hydrogen at 206.8 kPa kitten at room temperature for 10 h. The catalyst was filtered off through a sintered glass funnel, and the filtrate was concentrated in vacuo to 10 ml. Acidification of the residue to pH 2 gives a white precipitate which is separated by filtration, washed with water and air-dried to give 1.0 g (63%) of 2,3-dihydro-6- (4-isopropyl-4-methyl-5r oxo-2-imidazolin-2-yl) furo [2,3-bJpiridin-5- ^ka rbonska acid as a beige solid, m.p. · 189-192 ° C.

Example 70

Preparation of 4-mercaptoacetyl butyronitrile

Ϊ

CH3CSH + BrCH ₂ CH ₂ CH ₂ CN —B ch ₃ -cs-ch ₂ ch ₂ ch ₂ cn

Thiolsurric acid (49 ml or 0.69 mol) was added to potassium carbonate (93) (4 g, 0.68 mol) dissolved in 150 ml of water. 260 ml of ethanol was added and then 4-brorabutyronitrile was added at 15 to 28 ° C and the reaction mixture was stirred at room temperature for 16 h. The resulting inorganic salts were filtered off and the filtrate was extracted with toluene. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to give the desired 4-mercaptoacetyl butyronitrile as a yellow oil.

-205Example 71

Preparation of dihydrothiophenein hydrochloride _C H ₃ 4-S-CH ₂ - <H2CH2CN

HCI

> = NH-HCI

Hydrogen chloride was introduced into a cooled solution of nitrile in 220 ml of methanol for 1 h and the mixture was then stirred at room temperature for 16 h. The resulting product was filtered off, washed with ether and dried, yielding 55 38 38 δ of dihydrothiophenimide hydrochloride, m.p. Mp 189-195 ° C.

Example 72

Preparation of dimethyl [tetrahydro-2-thienylidene) amino3 fumarate or maleate

CO2CH3

i

N _Z C-CO2CH3

CO2CH3!

Dimethylacetylenedicarboxylate (0.45 ml, 0.037 mol) was added to a solution miscible with dihydrothiophenein hydrochloride (0.5 δ or 0.0036 mol) in 60 ml of methanol containing 0.3 δ or 0.0036 mol of sodium acetate in the atmosphere nitrogen at -15 ° C. After stirring for 16 h at room temperature, the solvent was removed on a rotary evaporator and the resulting mixture was separated on a silica gel chromatography column eluting with methylene chloride-acetonitrile (19: 1) to give the desired mixture of the desired acid esters. in the form of yellow oil.

-206 ^ O ₂ CH ₃ J - C0 ₂ CH ₃

Example 75

Preparation of dimethyl 2,3-dihydrothieno [2,3-b] pyridine-5,6-dicarboxylate oxalyl chloride

DMF

C0 ₂ CH ₃ C0 ₂ CH ₃

I

The Wilsmeier reagent was prepared by adding oxalyl chloride (0.25 ml, 0.0028 mol) to a stirred solution containing DMF (0.22 ml, 0.0028 mol) in 50 ml of 1,2-dichloroethane in inert N ₂ atmosphere. A 1,2 dichloroethane (50 ml) solution of dimethyl [(tetrahydro-2-thienylidine) · amino] fumarate (and maleate) (0.0028 mol) was added to Vilsmeier's reagent and the reaction mixture was heated to reflux for 4 h. The reaction mixture was treated with water to quench the reaction, made alkaline with sodium bicarbonate and the organic layer separated and dried over anhydrous Na 2 O 4.

The solvent was removed in vacuo and the residue purified by chromatography on a silica gel column, eluting with a mixture of methylene chloride-acetonitrile (19: 1). Crystallization from toluene-hexane gave dimethyl 2,3-dihydrothieno [2,5-b] pyridine-5,6-dicarboxylate as a white solid, m.p. 102-103,5%.

-207Example 74

Testing the herbicidal activity of the test compound after emergence

The herbicidal activity of the compounds of the present invention after emergence is shown in the following tests, where different monocotyledons and dicotyledonous plants were treated with test compounds dispersed in aqueous acetone mixtures. In these tests, the plants grew in suitable pots for about two weeks. The test compounds were dispersed in 5θ / 5θ acetone / water mixtures containing 0.5% TWEEN® 20, a polyoxyethylene sorbitan monolaurate surfactant from Atlas Chemical Industries, in sufficient quantities to provide an equivalent of about 0.16 kg to 2.0 kg per hectare of active compound when the plants are treated with a nozzle operating at a pressure of 275i8 kPa for a predetermined time. After spraying, the plants were placed in greenhouses and stored in the usual way as μ is done in greenhouses. From 4 to 5 weeks after treatment, readings and grading were performed according to the grading system below. The data obtained are given in Table V below. % growth differences

Rehearsal evaluation system

- no effects 0

- Possible effect 1-10

- weak effect 11-25

- moderate effect 26-40

- Defined damage 41-60

- Herbicidal effect 61-75

- Good herbicide effect 76-90

- almost complete destruction 91-99

- complete destruction 100

- abnormal growth, defined physiological disorders, but with an overall effect of less than 5 on the rating scale-208In most cases, the data refer to one test, but in some cases, values are averaged from more than one test,

Plant species used - Table V VI

Great rauhar (Echinochloa crusgalli) 1 1 Green fly (Setaria viridis) 5 2 Purpuma oyster (Oyperus rotundus L.) 4 3 Wild oats (Avena fatua) 5 4 Purevina (Agropyron repens) 7 5 Polish Popon (Oonvolvulus arvensis L.) 8 6 Shipwreck (Ipomoea purpurea) 9 7 Lipica (Abutilon theophrasti) 11 8 Barley (Hordeum vulgare) 12 9 Corn (Zea mays) 14 10 Soybeans (Glycine max) 13 Sunflower (Helianthus annus) 14 Wheat (Triticum aestivum) 12 Everybody (Uigitaria sanguinalis, L.) 2 11 rice The gut (Lolium, spp.) 6 Divina dressing gown (Brassica Caber, L.O.) 10 Sugar beet (Beta vulgaris, L.) 13

v

-209it

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Post-emergence test - Quantities in kg / ha

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»1 1 ο ο e ο e ο οοοόοο βΟήβόιίΙΝ Ο Ο Ο Ο ΜΙ Ο ο ο ο ο e ο β> «« · 0 ΙΑ « 0.04400 ΟΟΟΟΟΟ Ο Ο Ο Ο Ο Ο ΟΟΟΟΟΟ β ο α ο ία ΙΛ ΟΟΟΟΟΟ ······ • · · · · · βΝβ. «ΙΟ ΟΟΟΟΟΟ Ο ΟΟΟβΝ ΟΟΟΟΟΟ ο «η e ο ο ο Ο Ο Ο Ο Ο Ο • 4 · 4 4 4 ΗΟΟΟΟΟ ο> 0 r »· β« ια Μοκιαοα Ο Ο Ο Ο Ο ΜΙ ΜΙ ΟΟΟΜΛΝΟ Ο Ο Ο ΜΙ Ο Ο r »r» ιη <η · η ο ο ο ο ο ο μ »ο »» .Ββι ». 40 ΟΑ ο ' ο ο ο μι ία ο ο ο ο ο ο ο ο ο ο ο ο οοοοοο 0 Ο 0 ΙΑ ΙΑ 0 0 Ο Ο Ο ΜΙ ΙΑ Ο Ο β Ο Ο Ο ΙΑ β ο e ο ο e ο 4 · 0 0 0 ΙΑ 0 ΙΑ ... 444. ό ο ο ο Μ »** · ο ο ο ο ο Ο O Ο Ο ΜΙ Ο Ο Ο Ο Ο ΙΑ ΜΙ ΜΙ Ο Ο Ο ΜΙ ΜΙ Ο ο ο ο ο ο »» «Ί« ut r- 0 0 α «i ι ·» « Ο Ο Ο Ο 40 κ ο ο ο ο ο ο Ο Ο ΜΙ Ο ΜΙ ΜΙ Ο Ο ΜΙ Ο ΙΑ Ο Ο Ο Ο ΜΙ ΜΙ Ο Ο ο e ο ο ο e Oehh4 * Η r »ΟΟΙΛΑΗ ο ο ο r * ο ο ο ο ο ο ο ο ΟΟΟΟΟΟ ο ο ο ο ο ο ΟΙΑΟΟΙΑΟ Ο Ο Ο Ο ΜΙ ΜΙ ΜΙ Ο Ο Ο Ο Ο ο ο ΟΟΟΟΟΟ r * μ w ο ο ό Ο Ο Ο Ο Γ * «ί 0 0 0 0 ΙΑ ΙΑ 4 * ΟΟΟΟΟΟ «« ο ο ο ο. οο Ο ΙΑ ΜΙ ΜΙ Ι Ι ΜΙ Ι Ο Ο Ο Ο Ο Ο ΟΟΟΟΟΟ ο ο ο ο ο ο 1 · »ΙΑ Π« Μ rl ο ► "" μ η ο ο ο ο ο ο ο ο 1 1 ΙΑΙΛΟΟΟβ Ο Ο Ο ΜΙ Ο Ο ΜΙ Ο ί ΗΟΟΟΟΟ ο 0 0 0 0 0 0 ΙΑ 1 ι e ο ο ο ο ο ο ΜΙ Ο Ο Ο ΜΙ Ο Ο ί <400,000 1 ο 0000000 1 1 Ο Ο ΜΙ Ο ΙΑ Ο Ο Ο Ml ο ΜΙ Ο ΙΑ ο ο ο μι κ Μ »ο ο Ο Ο ΜΙ Ο Ο ihNHHOO 1 Ο Ο Ο Ο <4 <4 Ο 4 Ο ο ΜΙ «4 Ο Ο ΜΙ Ο Ο ο ΜΙ <4 ι ο ο ο ο ο μι η ΜΙ Ο Ο Ο ΜΙ ΜΙ 44 L Ο Ο Ο Ml VA 44 ΜΙ Ο Ο ΜΙ ΜΙ 44 1 Ο Ο Ο Ul 44 Ο H Ο ΟΙΛΝ 4 H Ο Ul Ο Ul 44 Ο 1 * 1 ΜΙ Ο ΜΙ 44 Ο ΜΙ i ΟΟ ΙΛΝΠ ο Ο Ο IflNHO Ο Ο Γ * ΜΙ <4 w ο Ο Ο ΜΙ <4 f4 Ο Ο  <4 F4 Ο Μ U-. ---- 1 γΗ 1 1 · 1 1 Η Η 1 1

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Post-emergence test - Quantities in kg / ha r

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-211-

e e o o o o o o o o o O o o o o o e o o o o e o fr 0 »φ σ * Φ» M <v o o o o o o HHO o o o o o o o o o e e o. o o o o o o O O o o O O 9 9 · 9 9 · <fr < <0 (s 4 1 * 1 M «J 9> β * 9 * f * o

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Post-emergence test - Quantities in kg / ha co o

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212 '

Post-emergence test - Quantities in kg / ha

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k \ J

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213 '

Post-emergence test - Quantities in kg / ha

» d ·} M β O IA IA m oooooo oooooo o o o o o o H '} rt rt rt o o e hhhhhh O O O O O O MN M rt rt rt £ i 1 o o e o e o oooooo OOOOOO β β o β α o Φ A> O 4t <A 9 * o e »r>« r «i o o o r r o 9 · 9 9 »rt rt n cj J rH 1 1 1 h! A o o o o e oooooo oooooo oooooo H! AtUNOOO O R O O O O «ΝΝΗββ F * F * rt rt rt O 1 o! 1 o o o o o e H! | ······ Φβ-rtNOO 1 (T \ i w irt e w ic e and «r» r ·. «A ·? m OOOOOO oooooo o e o o o e «I K P * P * O O R R O O O O • A «<M rt O 00 i 1 ! irtirtotrtoo OOOOOO OOOOOO O O o o o o 1 and r r o r o o R R o O O O o r% o m R o 9 · 9 · r »<β IA M o- 1 S i «irt irt irt o o oooooo oooooo O o o o o o J r * o o ia <4 o oooooo oooooo o o e o o o ω 1 1 1 1 1 m 1 1 1 oooooo oooooo oooooo o o o o o o ί «e f» <n h o o r * o o o oooooo o o o o o o d · 1 1 1 oooooo oooooo OOOOOO O O o o o o S M O O O O O oooooo oooooo O O o o o o Ks 1 • 1 oooooo | ...... 1 F »M rt O O O OJ 1 1 1 oooooo 1 ...... 1 OOOOOO H ' 1 J OOOOOIA j .FFFO oooooo oooooo o o o e o e t * M rt O O O o r * R R o o * -9 rt rt rt β • • <9 O O IA rt M O O O «A R« J O O O IA R «i O O o «A R O and —I o 'O O Irt M <o n O O IA <M O R o o ia n <e rt o O IA «M Ό R 'O' «M R o O O «A O R O O O IA O R O O O IA <m r4 O O »-1 HM ! M ' R R R

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Post-emergence test - Quantities in kg / ha co ·

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OJ s

I <-l

O O O O O O M «ri <ri <4 M M o o o o e o o o o or e IA O IA IA IA IA • i «1 O O O O o e a o o o o · o> o * <o F o O «ri R R ia e »o * O O  · O o O O IA O O rri Fri O O O O • «· · o o o o o e e o e a o O O O O «ri IA O O O O O O O ···· «« o o o o o o M O e e O « o o o o o o o O O O O o o o e r * »« 0 «u e hbNHOO ό ΟΌ o o o * o o o o o o o o e o e o e o o o o f f ia a o o o o o o r * o o o o o o a m m ia o o o o o m o m a e o o o o o F F 40 F «1 o O 0 * -ri M O O o o o «N4O O O O O O o o o o o o o ia ia o ia o o o o o o o o o o o o o o F f «f m a M *. 1 «Ni * F F 'F F «M o o o o o o O O O O O O O IA IA O O O O o О О О o o o o o o β M z * β O O r «ri o o o o r * «ri ri »O O o o o «ri o o o o o o O V Q> OOh o o o o o e <900000 О О О O O IA O o o o o o o F «« F »*» o a f f m o o o o o F F F «4 F F F F C C F e o o o o o o a o o o o o ΙΑ O IA O IA IA O O O O O O O o <o o o o R Fri O O O O О О О o r * <F * F «f» IA M a o o o o o o o o o o o o «Ia ia n a o o o o OOP * o o o o o o o o o o o o t »* e o o a o o o R O R o o o o o o O O O O O O o o o O IA IA O o o o o o o «F w o o o hAHHOO o o o F F IA M o o o o r * μ i o o o ia n ci O O O IA R «M OOOIAOIAR «ri O O O F »A« N 1 e o irt <m »o n O O IA «ri ri) R O IA O r * ia «a« o r O O IA «ri« ri R [ΟΙΛ CMHO O O IA «ri R O O О ΜΛΠΝΗΟ О o ia «ri r o o t. ** Fri. • ri Fri __

Φ • Γ3 β

Φ

Ό β

• H • d

Φ

Ha

1 1 o Ο γ-1 1 ι 1 risi 1 Ρ • Η o • 4- Λί · Η pil Ά 1 -Ρ 1 N 1 About β P OJ Φ Ο OJ Φ • 4 · d O l 1 z ~ s 1ι 1 B Ν LB 1 ♦ d OJ lOH O O 1 • rt Ο 1 ι-l · · Η 1 «rl n ω lo I ω ιο • Η β β r-1 r-1 P • Η Χ4 | 4 Χί ι Pl • H ι-1 • ri • rl «rl 1 About z-> Οο Oh 1st d 4-3 4-3 ^Γ β 4 · 1 rd 1 1 Η P OJ 43 β Φ Φ »rl '• s ΙΓ \ · Η OJ ΙΟ · r-1 P · 1 Φ-Η β β r-l 1 1 β -P 1 β o O β r — 1 1 1 O OJ ι-1 · Η CO., LTD r — 1 r-Ι · Η N ω 1 Φ s ~>. 4 N , TJ C • ri ♦ ri «d • ri X 1O M 1 1 d H + · · · · · • Ρ • P -ri -P 1 O 1 «H \ _z r-1 xJ • rl φ r-1 4-3 Φ ΦΗ d 4- 1 1 ♦ H · Η -Ρ Ε Ο Ο β Ο Ο β v_z and Č> r1 Pl β Φ 1 N 1 I Ν · γ1 1 ι · η d Q5 O · Η S ch d · η ω in d -Ρ OJ H CX P 1 -P 1, 1 τ (β β 1 Πβ Ο 1 • ri * r1 0) 1 Pi OJ c5 W | H · Η ι — 1 d Λ · Η Λ4 ω 43 · β β ω O 1 £ · Γ1 | · γ1 G · Η Ρ • ri G-rl • H Φ -rl · γΙ • rl N O • rJ ϋ | Perl +3 Η Perl β o β ι — 1 43 Oh • rl W 4-3

-215K \

H o

rH r

i

I

I

I

I

I

I

I

I

I

And a

and a

I

I.

I

I

And e o o o o o o

© «« MAN tl · * »*» » o e o o o o o o o o o o o o o o e o o o o 4 »o e o o o o a o e »o o o o o o «B β» β * O * β * M tl · »o» »» » o * φ σ * r * m m β * φ r * β e o e-o o o o β β o α o a e o o o β e o o a o »» »» From » o K r · »<e <o» <vn o o o

Table V (continued)

Emergence Test - Quantities in kg / ha

Ολ

EN <0

ΙΛ ro

OJ r4 r “t

O t

I

I

I

I

I

o o a o o o ooooeo e e o o e o σ »40« φ r * r * o o e o o o e o o o o o o "" o o o o o e σ · «o» r w o o o o o o »» O »« r »< e o o e o o o o o o o e * <► «r * o o o o o o o h * r * r * r * e e o o o a o e o o e οοφο o o o o p a e "" o o «« 9 «r * r * · <M o »* 0 * o * "" o r * «i o o e »C · n o o o

I

I

I

I

I

I • i

I

I

I

I

O O O O O O e o o e o o e e o o e o o o e e o o O »« p * «A <SI O K »» O O 0 O »» 1 * «M O O o o e o o e «MAsf NO o o o o o e OOOehsf o o o o o o «O m m o o o o o o e o o <# M zt O O O

O O O O O O O O O O o O o e o e o o e o o e o e »» O M O O »» »» o » O O t »*» o o <Jf »» $ NOO

000 * β O <Λ 9A «M e tft <u« e m 4 »4 o o ° ° ® “» Ή W o o o tfk m m O O ΙΛ N-OM o o e e O (A O tft f * «4 ΙΛ N« O rt w a tn «m O m <M Irt «O« rt O O e «4 • rt

I

OJ H • H P 1 1 ri H • h -d P H Φ H Φ a> S o T3 e 1 K » β 1 J rt (U z— \ i d p You 1 r-l «H d β H e β • H 1 P. H H • d Z— \ About 1 p Φ Pil POI O H p «and λ: 1 O O H w N rt β p • H rt I O H P 4 1 H Ea ^ ζΐΛ β

I I

Oh 1 z- ' that Λ4Η rt 1 • H OH β o 1 1 fiH N 4 ΙΛΗ r-l H v_z I τ) ^r ' 1 1 r-l H rt d · OJ 1 H i — 1 H p o v_z 1 o φ 63 oj + E rt r; v_z I d rti r-l 1 d- H rt H Z — S 1 13 fi P Pil r-l H H Φ s_z 1 H 1 P p «CJ O ί ω About 1 rtd rt • H fi O H H Oh P ^ rt fi r>

I

1 1 z- \ 1 o o rt 1 J *: r-l N Λ! <0 OH H O 1 1 fi 1 1 ΙΛΗ P 4 UH 1 d rt K_z 1 H ra h fi 1 r-l p 4-3 • rlr — l H OJ H H rt P O P P rti fi φ N O r-l Φ H H With rt / s H G H P 1 d H .13 1 O O ^ - • H fi Φ d- «rti 1 Brl e 1 Cape H ΗΉ H 1 Fi d fi H 1 P ω H H rrt POJ (!) fi Pf G H O 1 G rt O H -P P O 1 P P 1 Φ Pirt li) Pl P-iOJ S

me

216 · r

H · t

KV H J t · i 'trt ·.

i

e e o o o e o o e e o o o «k o e o o MhAlANN o o o o o o O O O O O O o e e o o o o o o o o o , o o o o o o o β * β * φ o o o o o o o o ^ ANHOO o o o o o o o o o o o e e o o-o o o O <0 O M M e o o o e o o o o o o o o

O trt rt, d 'hO

A4 σ 'o »e» σ> «r» ia ooooe <

CO., LTD

Z ~ S rt d

+5 ω

rt

G rt o • H r — I rt

IM ω

G • rt> O • rt

H

Oh

Sil

CO «· e ·« t ~ e · »

I n

T3

G rt o

• rt

Mr

Φ r — t CO O P <

Ra • ra

G rt i>

• rt • P • rt

G, ω

H t t

LG

I o »o o e e» n

I ι e o o β e e eh i ......

ι o o r * r »« e o

K \

C \ J e o e m ia «i o o ia n> 6 a O IA M« A O O oooaan O O ΙΑ ΛΙ «A lA O IA N H O O

ΟΟΟΙΛ AN β O U) N «O A OANHOO

O 1 · · and - ^ 4 1 1 IG ¹ 1 s ~ \ 1 1 O 1 1 * Fb 1 1 1 1 rrt rt- CO »rt o CO., LTD rrt z-. o rrt -rt 1 Λί P I N 1 Λ2 • rt rrt • rl • Cape G H O O • d- rt o Oh • P-rt co P -rt 1 Atj 1 rtAi O G Φ Ie P irvrt rrt »rl * rt • rl Έ T l Oh B «rt Φ 1 G • rt ε g rH 1 rd 1 rrt o P) 'rt rrt rt > Γ · Η • rl rt- O rt • rl rd O 1 Ή rt 1 rrt 1 G l P -rt Φ G CN -P Mr 1 rd O rt rH Π5 ig a) Mr • n Gi 1 Φ • rt ω • Cape Vine • rl Tl B 'rt Mr O O E H Gl rt 1 P ^ * r1 1 l * d Φ N CO | Φ r1 o ω o E CN ^ h * rl • ra • rt Λ! <0 CO., LTD • rl G-rt P · Η t rrt Mr 1 o l • rt P P-iE P rrt Gi 1 P r ~ 1 rrt O • H • rt- 1 '' 'P Φ O -rt rt • rl About CN rt • rl • Cape N • d IG rrt a N 1 Mr P N 1 G P Gi rt Φ 1 1 «rt rt | • cape (N • rt Φ • cape O-cape Φ o -d CN H G «M co I t P a ι ω p E G-rt 1 'rt -rt that Mr 4 o Oh 1 cape A4 O 1 Gi E CQ | P Ie Mr rt v-z ω M co <-> About Λ4 co O -rt P • rt I Φ «rt ♦ rl Mr 1 Λ5 • rl • rl 1 1 -rt CS3 | rt o i a h -p (M CN O Mr o CN LG G o • cape (N Mr

ΙΆ t — I

O and —I

217 Post-emergence test - Quantities in kg / ha σ 'oo

LA

OJ r-l o

Φ • ro

C

Φ • ro

O • H • d

Φ ho

o o o e o e o o o o e o O o O O O O 0 «J. m M M mb ri ri «wh M »H» 0 z. 0 O o o o o o o c »o o o o o o e o a o o e O 9 O o * 9 o 0 0 0.0. O 9 9 9 o o e a e o o o r »0 0 r-t ι-t« H e o e o o o e β β β o e e o o o o o o ό r * <m o «Ό o o o o o o β «)> ΙΛΝΟ o o o o o o 099999 o o o o o o o o o o o o o o o o o o e 0r * Ό ΙΛ 0 9 0000.1 * α o β β e e O 0 0 0 0 0 O O O O O O o 9 o m ^ 4 o 0 00.00 0 0 a r »r * rr e e o o o o O 0 0 0 0 9 O O O o o 000000 9 O O IA IA O d d d to

0 o o o e o o o o o o o o o o o o o 0 0 0 0 0 0 * o r * o vn o w ΙΑ H M O O O o o o o o o o r * e m vn w o o o o o o o o 9 r * r * o O O O O O O 0 0 m 1 * 0 W O o o o o o <d d o o d

o o o o o o Oh O o o o o. O O O O O O «E M «4 O O O 9 <vn 44 o o

o o o and vn ra Oh o oiflvn « o o o o and vn o o m «m« e r » Oh o m m o vn O O O IA <W 9 o u> nm OO Oh m n - a o β G «NH« • 4 ' • 4 O * 4

1 O 1 W «H 1 ii 1 1 rt «rl Oh β 1 <rl OJ -P 1 r — 1 I • ri o Β1 β 1 • d to, rt CL 1 o • rl ι- rt N O 1 rš • rl No β Oh o ΛΙ CL • rl> • H 1 rt • rl B O-H N to -rl Ο 1 Φ 1 ΙΛΗ β CL • rl -µ r-l • rl λ: c β OJ N ; fr 1 · ι — 1 · η o 1 Φ Φ 1 Οζ-'χ'β CL 1 β • - ' i — 1 β r—) β OJ B Φ rt · 1 r — 1 · Η Ο O Φ t • rl «rl Φ CL 1 1 -H ΙΛ · Η β Η M, O <\ J -P * d it o OtO 1 1 β Ο • rl r ^- x 1 Φ · Η · Η this one to 1 OJ · · ΗΗ | O H P S ι — 1 Λ! • rl J * J <r · rt • rl -d X) rt · 1 Ή o 1 Ο 1 Orl ^ r-l • Ρ · Η Ο ν_ζ LA β r — 1 rt · n rt 4 1 -rl to • rl Ι ι-1 β 1 1 -rl three rd 1 rt rM LA β β -P ε ο Olr — Ιτί β 1 η «d to 1 1 «rl · γΙ Φ 1 Ν · Η | • rl «rl · Η LD • r4 · Η β OJ H «d -P B 4 d Λ that -t · ³ r — 1 rl 1 CL B · Η 1 • rl · Η O 1 ι «d β Φ O Φ that O · Η -P tol P H J * tol ι-1 · Η -Ρ rt That's it • H β 1 o • rl Φ Ot | • rl • Η β rt β 1 rt -H Oh CLAI PJ o | B n β o | CL-rl β trt ii «d ^ J

OJ and —I

218 ·

OOOOOOOO ····· ♦♦ · ΛΛΗΟβ β> o o o o <o

Post-emergence test - Quantities in kg / ha and —H

Oh

H co co o

IT \ etre «

OJ r-1 O i β e o o e o o

omiaomiaoo ί'ί '.. HOHO o e o o e o ® «8 9 · rt 1 * 1 M o o o o O O »>» «Rs *. < ominmiA m e o »r * *. 4 ia · η4ο e e o o o o o o o o r »m e o o o o o · »9 * O O O <4 o o β α α e o p »r» m «<a o o o o o e o o . "" .. o e e o o e o o o · «o r *> o e o e o o e O O «4 W O O o e o e o e o o «r o w o

° ortooooa rt.eeoooa o o o o o o o o o o * r o t o o o o o o O O O o <ft F » ooiaiauiooo o o o o o o O O O O o o * ^ - BrtWrtOa «« HeirtO a e * <e «# m a ΟβΜΙΑβΟΟΟ ^^ »400,000 OOOOOOOO i o o o o O o ' o o o o o o o o o O O O rt m a o o o r * o <r «4 w o O O f * R «4 o 222® “'··' *« .. 22 ^{οιη <} «* ^ κ * 2 ®®rt« Mrtoor, βΟβΛΠΝ o o tn <4 o m o and «4 * 4 o o QO OiflUN o o m <4 o m o M (4 «4 O O «4w · · ·. . * 4 «4

o P 1 o P and ra 1 14 1 | 1 PiOJ O Oh Oo P O Ή Oh 1 N N • H H Pl ra p N o c PoP P o rM 1 Φ • H «Φ I 1 P N OzM 1 Λ! , O el · LAP • H • H p TD LT \ Oz- \ 1 P 4-5 p d 1 P 1 P P eh 1 P (D 1 eh P OJ • H P LAP • Γ3 o 1 P P O I 1 P and ~ 4 p p P · Η r — 1 Φ N Pl • H r — 1 • H ip • H ε ra P ι - 4 P • H 4- ⁵ · Η P And P -p I-) +5 O Φ p Φ p Φ er P ra p Φ N h> P E O S 1 E P +5 a ra 4-5 Pi 1 N « P · Η P φ and p ra Oh la ra ra • H 1 4 ^ Mr el · P P P 1 P P PiOJ Oh | 1 E · Η Pl P Ή ra O I IZ r-M ra and - t · H -P 1 OJ • H E P P o • H • H P 1 O PiP EP Pira P Oh pxm

I

1 P LA P 1 l ra 1 o 1 P N el · • r4 P • ra ra 1 E-H Pi p H P 4-5 o -ra • ri 1 O p ra Pi OJ ΛΙ P-. · Ι-4 Oh 1 -H O 1 P O P H Ol Pl ra i • r4 | 4-5 o Λ4ζμ and about ra 13 o p ra io ra o P P P p K 1 • P P-H 1 o p d- 1 P P O 1 Φ ^ .Z LA p Φ eh P 1 1 P ra P 1 OJ P P P • r4 P P 1 P O Λί Pi P P acre 4-5 L3 O 45 p • rti φ ra ra p Φ P ol 1 E P Λ-J P EP

-219

Example 75

Investigation of the herbicidal activity of the compound ladder before emergence

The pre-emergence herbicidal activity for the compounds of the present invention was performed with the tests described below, in which the seeds of various monocotyledonous and dicotyledonous plants were mixed separately with the potted soil and sown on an area of approximately 2.5 cm from the surface of the earth in separate vessels. After sowing, the seed containers were sprayed with a selection of an aqueous acetone solution of test compound in sufficient quantity to provide an equivalent of about 0.016 to 2.0 kg / ha of test compound per container. The treated seed containers were placed in a greenhouse, watered and stored accordingly. the way it works in greenhouses. From 4 to 5 not divisible after treatment, the tests were completed and each vessel was graded according to the rating scale given above. Herbicidal efficacy can be seen from the test results given in Table VI below. When more than one assay was tested for a given compound, data were given as the mean of the assay

220

ΒΑ β β Ο Ο Ο |

Ο Ο Ο UI O ο, ΜΛΙΟΝΝ ί

Μ Ο Ι Μ <<Ο Ι Μ <<<<

ΒΑ ΙΑ β Ο β ΙΑ ΟΟΟΟ β f »ί> Ό <ΙΑ Ο Ό ΙΑ« H

ΙΑ Ο ΙΑ ΙΑ ΙΑ m ο ο r * ο ο <

Ο Ο ΙΑ ΙΑ Ο Ο ·· «« ··> β r * ό <<»!

ΙΑ ΙΑ β Ο β ο

......

ehMUM «!

Ο «0 9» Ά ο ο ο ο ««. · Β »α« ι *

Ο β ΙΑ β «· · · * - ΙΑ * σ ·,» «ι w w

IS..HOO

Ι>, β * Ν β Ο ο β ο Ο Ο «Ο Ρ>.

Φ

Λ \

ω ω

β • Η> Ο • Η ιβ

Ο

I η φ ϊ> · Γ3 «5 Φ

Ο ο • Η · β ι—) β

Χ>

Φ φ

F? β

Ά σ>

C0 οω

D \ d

Κ \

Ο Ο Ο Ι Ο Ο.

Ο Ο ΙΑ ΙΑ ΙΑ Ο 99 «r * r * m

99ΑΙΛ

Ο Φ Ο f * ΙΑ Ο

Ο Ο Ο Ο ΙΑ Ο Ο Φ φ ο * c ια ο e ο ο ο hWOeee

OOO ΙΑ Ο Ο Ο ΙΑ OOOA ^ IA «!

e e ο 99 99 99 99 99 999Α9 <«0 Ο 9» <0

ΟΟΟ1ΑΟΟ ΟΟΟΟ

999βΝ <99SA ο ια ο ο ο ο ο οοοο «« · ·. ·· '····

9Μ »9 * Ν I * Ο Ο ΙΑ ο ο e ο ο ο ο ο ο ιό ο!

Φ • ο β

rt>

• Η ρ

• rl

Ρω

Η

Ο) γ4 •

Η

Ο

Μ

99 Ο ΙΑ ΙΑ ΙΑ Ο ί 99 ΑΑΑ «9 ι

ΙΑ ΙΑ Ο Ο Ο ΙΑ β · Ο Ο β Ο Ο ί «Ο Ο · Τ ΙΑ ΙΑ ο; Ο ΙΑ Ο Ο Ι Ι. ΟΟΟΟ ο r * r * ια »ο • · · · φ * <- ΙΑ Ο ΙΑ ΙΑ ΙΑ Ο ·· «·« · I ΙΑ ΙΑ ΙΑ ΙΑ ΙΑ Ο ΟΟΟΟ r * f * ΙΙ »Ι » • · · · 1 r * ι * »<κ ο ο * οr »µ Ο Ο Ο Ο Ι Ι Ι Ο Ο Ο <Μ Ο ο Ο ΙΑ ΙΑ ΑΙ < Ο Ο Ο ΙΑ Ο Ο ΙΑ «Μ rl Ο Ο 1ΛΝ4 Η Ο Ο ΙΑ » ΙΑ N Η Ο Ο Q Ο ΙΑ «Μ Μ fV • · · ·

99 ^ ΗΟ

Ο Ο Ι Ι <<Μ Ο Ι <Μ ΝΗ Ο Ο

Φ · Γ3 α

φ · Γ3 β

♦ rl

You

Φ

I 1 (Φ 1 1 1 φ · β ω 1 LTV— \ 1 ο ι βΗΉ OJ 1 rrt ρ ο I β ι .Λ I 2 ^ Β · β Φ β CJ ι Cu (VI Ρ d Ν • Η · β β β Λ ι ο Ο I ο 1 Φ Φ Β · β · Ή ο Ο 44 Ν r »ν Η X) 44 β Φτ) Η Ν ω · β · · η • Η · β ω Β Β · β -Φ -Η 44 C 1 Β3 β Pi C β ρ ι η ω 1 Ο ζ “\ Β · β Φ Wd Ο · Η -4- 1 rH 1 (β β 1 β Φ 1 Ν 44 · · β I ιΛ · β ΡΛΜ γΗ r — l φ I 1 β <χι 1 β Ο 1 ο Fl Ή χ) fl) β 0J · · Β ι- <· β N Ο ρ • Η Ρ <.β44 φ • Η γΉ • Η Τί • rl Μ | Ο Ο β 10 Ρ r4 · · Β · · Β I 44 tJ | Φ β · β β ω • β Φ Η Ν Φ Η d- ο ι β β 1 Φ φ Ρ e ο β s ο | \ OOJ β φ ! ^Ν Φ 1 to 1 ΙΛγ-) * · Ν | ι — ί <β Β d- Φ Ρ ρ • 4 φ V0 1 · Η Β · β Ο Ο • Η 1 1 ^r d rt 1 1 TS Η β β j ωρ Ρ ω | r-Ι · β β ω α ή · η • Η 4 44 1 Φ • β • Η Β · β • Η Β β Η Ρ φ Ho Ο pj Β ο | Ρνβ ρ ο | 1 ΡτΗ β

4 1 I ο I Ν · β Φ 44 τ5 γ-Ι • β φ • Η Β 44 • β ω Ο 1 β β (VJ · β Ρι 1 Ρ ο Ο ο Ν ω, γ • β 44 · β 1 4 Ο β 1 ' ν_> tf \ rd | 1 · β φ (V Γβ β β 1 • β * β • β W | | Ρν) ιβ • β φ · β φ ο | | β Η ω

-221

J e e n »o o m o o o o o o o o o o o o a o rdi» .nm <! Go iš ^ riooo »cZ m o ό o

1 t it ' o o o o e o o e o e o o o e e o o e rd 1 1 * 4 »4 W O O O e e e o o e K o? «U * 4» 4 Oh • 1 ^: oeoooe o o o o o o o o o o e e O o o o o o H t m n o «e o «IHOOOO »« «R * i * in 9 »θ '9 * 49 r * < 1 o o o o o o o e e e o e O O O O O O • o o e o o e 1 rd t 1 0 * 9 * * 9 * r r «p4 9> 9 <uhoo - 9 »9 9 * m rt <4 999tfRN i 1 o o and e m e o o o o o o o e o e o o o o a a o o o 9 1 a <0 · «n« «n n ri (U N O O O O ' 9 * 9 * 9 * «1 W 4 * 1

rt

O bO

Table VI (continued)

Φ d

• rf> O • rl rd

Oh

I rt • Γ3

O • rl β

φ fd

P »φ

• o

P rt>

• rl

P • id

P.

ra

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~ 1 1 1 and o o o o u i o o 1 9 9 99 H O 1 o o o o o o o o o o o o o o o o o o «« .Nho σ · * «n« h o 99 9WRH 1 and oe «iftoee O O O O O O O O O O O O O O O O O O 1 9 Ift R H H e 9 1 «J o o o o o O O o 91 O O 9 * o r * f * ui o 1 and o e o o lf) 1 · · · · 1 9 »9» 9 * 9 1 o o o o e o 9999WO O O O O O O »» · * -E -e <r o o o o o o 999990 1 1 O Ul OOOOO ^w '1 99 hNHee 1 000009 O O O O O O e o e o o o 9 »9 <U O O O «A a ·« m o e »« «f» · «n ! o a o e e o O O O O O O O O O O O O o o o o o o b 1 e> o o o o 990000 9hhrtwe 99h9NH 1 aooeooe ⁿ '1 9 9 * O <91 O 1 o o o o o o 9 · <9 O O O O o o o o o o 9R NNNM O O O O O O 99RRUH 1 1 O O o o o o o ^v 1 <1 9 f * 94 O 1 1 1 OIA OIA1AOO O O O O O O o o o o o O o o o o o O > 999 ^ 000 1 o r * o o o O 9 «4 o O O O O <4 O O O • 1 90 OIARN9 _j 1 O O Γ? 1 O Ul «4 M O O β 009RN9 O 9 N 9 R * 4 Ul <4 »4 O O O O OtflR N9 O U1 <u 9 R H Ul <4 »4 O O O OO U1RN9 O irt a R h Ul «4 o O o M t.7 ........  · ........... ---------

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o o o o e c » e e e ^ t e ° 'o o o o o o o e a a o o «E» ♦ rt rt «4 rt <rt O O M k «a o o o · «Irt rt rt rt e O <3 O O O O o o o o e O e o o o e o o o e e o e ΟΙήΝΟΟΟ r * e r r o o W «NNNO e e t »· * rt« m

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ο о о о о о о ·· * ·· « ΟΟβΝΜΛ o e o o o o oo r »r r m o o e o o e o h » o o o e e e * o r * r * r * O O O O O O o o oo o e 6 o o o o o O O O M o O o o o o o o i φφφφοο o o o o o o O O <R R o o o e o o o o o o o o e o e o o o o o e o o e O O O M> R <M o φ p * «r οι e ό o o ο o o e »r» Ol O R i o o e e o o o oo o o o o o o o o i i 1 o o o o o o rt rt -0 rt rt o rt rt rt rt rt o r * o 04 o o e 9 »40 f * t * R o o o o e e e o o o o o o o o o o o o o o o o <0 o o «i e e O e N R O hhOOOO a "cape" "" * o o o o o o o o o o o O O O O O o o o o o o e o o o o o O O M O O O rt 0 * rt 0 · <? <r o o o o o e o o o o o o o o o o o o o o o o o «« J a rt a o o * o e rl < M o o o o o o r * rš <<r O O O O O O o o o o o o e e o o o o o o o o o o r * r * m e o e * Φ O 04 O a o o o o o rt rt «m ·« «r o o o o o o o o o o o o o e o o o o a o e o o <R 04 M R O rt <r -r rt o r * ui «m e o «T N rt o o a

e o o Oh Oh e o Oh Oh Oh o o o o Oh Oh o o o o o o 0 0 · 0 • Sb «l R o o Ol R Oh o e -T rt e Oh o 0 »O -4 · 04 R O O O IA R Ol Ό o Oh IA R <14 O o IA rt rt rt O O IA R OJ Ό o m oi Oh R R Oh IA Ol * A R O IA 04 «O R R O rt rt Ό rt rt IAMH Oh Oh Oh IA Ol R Oh o IA M R O Oh o rt M rt β O O

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226 ·

Table VI

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1 OJ 1 1 1 1 1 0 0 1 0 1 1 1 1 A * rt 0 ra Λ! P OJ d) 0 1 z-s A • Cape T ra, hd-rt Pl 1 S N Λί A • rt P> rt cape O G 0 0 1 • rt O A 45 Φ A 4 AP ra ra φ 1 1 G Φ (!) s 0 • rt PJ 1 el · Lf \ A • ra B 1 N '—S 1 a rt 1 Ori K_z 1 T Mr 1 • 4 rt 1 A G C d 1 A 1 1— | «Rt P Φ 1 T -p OJ -rt-rt-rt LfVrt OJ • Cape A W • ra 1 a «rt rt 1 P T A 1 1 G-P P O G Mr • <_z Cape S G z-n Φ> rt (D OJ A «rt Φ r — 1 Φ N -rt • rl 1 Pi * rt -rt + E rt ra • Cape T G • rt G ra p T s ~ \ 0 1 +5 's 1 0 «rt A P-rt -rt P 1 T 0 Φ M POJ O t d- ra, v. • rt P A P Φ e) - «rt 4 * 1 i ~ a N-Z Pl 1 P z-n | rt P BOO Mr 1 G-rt 1 O O-rt P4 | AT rt Φ And ra, hj l A-rl G that n ra G n- '«rt -rt Λ! S er rt a ra • rt 1 r4 Mr • rl Uz — V 1 PcB ra 1 1 T G Mr P-OJ -rt rt 1 OA ral 0 -rt G ra A A A rt 0 1 P P - + | .rt • rt P I -rt • rt • Cape G -rt P ' p 0 Φ E ( 'it. Mr O p., C \ J p Oh PlA P EH p, ra g

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-228TaMiva VI (continued)

Pre-emergence test - Quantities in kg / ha

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1 O ΙΑ Ο ΙΛ ΙΑ IA 0 • 9 d d r * o ία 0 000000 0 9 r * m «a * 4 rt XJ 00 'them 1 O O O O IA O O OOOOOO 03 | ····· «* O- 1 0 «0« «J r * t * w 0 f »<0 0 o d 1 000000 OOOOOO ω c U) ί 999999 ····· « 9 9 O h »9« 4 • H > 0 • H OOOOOO H LA 0 0 0 0 0 M Oh w 1 0000000 OOOOOO 1 | . ····· * · «···· ii i 9 9 r * 9 m 0 0 9 9 O * n r4 O rt • ro β t 0000000 OOOOOO Ci ⁴ · 6 ΚΛ 1 9 9 9 9 9 9 IA 9 9 9 O Γ · R • H β 1 0 0 0 ΙΑ ΙΑ IA 0 o fj OJ 1 9 O O N 9 IA O Pt rt 1 OOOOOO OOOOOO • ro H 1 9 9 O 9 f · 9 9Ma «4O β 1 > • 1 O O O O IA m N 0 0 IA vn M 9 Ή rH 1 O OO IA C4 9 m ΟΙΛΝ444 • P 0 1 O O IA NH OO IA M W O O O • H M and M * 4 Cm w H 1 H 1 • rl O CL LO O rt 1 β 'd 1> ^c Pi 'rl d- rt · Η os and dd to H h -d 0 rt • d 1 • d a β β ω 1 OJ C-. 'D' d 'd • ro LA I -P 0 1 ΛΗ β 0 rt β CJ 1 rt rt 1 ω 0 cl 1 ia ω 'And' D o | To that O O 1 H β 0 β n ω ^> Αί • H H I rt • d Ud • d • rl rt- £> I O-d rt rt β 1 s'- ' 4 1 βΑί h> • rl r-l r — 1 LAH ω CL H «r-l 1 1 d C O -P β Al d β O β «H 1 HH _r P Pt Ed tfll-Pd β 1 1 -rl • dl rt O rt From LAH OB NAJ

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- 231

P-1356/84 1312-A-246 Hours 29,434

Claims (1)

PATENT APPLICATION 1. A process for the preparation of imidazolidinone and the imidazolidinone formula: in which RH, alkyl CH ₂ C = CH, nC-JH., CH ^ Hg, CHH (CH ₃ ) ₂ , N = C (CH ₃ ) ₂ , CH ₂ CH (OH) CH ₂ OH, (CH ₂ ) ₃ C ^with CH, CH ₂ CC1 ₃ , CH ₂ COOC ₂ H ₅ , CH ₂ COOH, CH ₂ COOCH ₂ C ^ H ₅ , CH ₂ CH ₂ - ^^, CH ₂ CH = CH- ^ 2y CH ₂ CH = C (CH ₃ ) -C ₃ H ₅ = C (CH ₃ ) ₂ , CH ₂ CH ₂ - | ^ J- CH ₃ , CH (C _g H ₅ ) -COOCH ₃ , CH ₂ CH ₂ C (CH ₃ ) = CH ₂ , (CH ₂ ) ₉ CH = CH ₂ , ch (ch ₃ ) c ₆ h ₅ , ch ₂ - ^ -och ₃ , ch ₂ -0-ci, ch ₂ -0-no ₂ , ch ₂ cooch ₃ , CH ₂ -CHH ^ CH ₃ , (CH ₂ ) ₃ COOC ₂ H ₅ , CH ^ CH ₃ ) COOCH ₃ , CH ₂ CH = CH-COOC ₂ H _[ 5 ' HCO CH. (CH ₂ ) ₄ COOCH ₃ , CH ₂ - ^ JC (CH ₃ ) ₃ , CH ₂ -C (Cl) = CH ₂ , n-CgH ₁₃ , CH (CH ₃ ) CH = CH-CH ₃ . CH ₂ CH = C (CH ₃ ) ₂ , CH ₂ = CCH ₂ OH, C (CH ₃ ) ₂ C = CH, CH ₂ CH ₂ l ^ (CH ₃ ) Ιθ, -C (CH ₃ ) ₃ , -0, nC _1g H ₃₇ , nC ₄ H ₉ , n-CH ₂ -CH = CH-C ₇ H _{1 g} , nC ^, CH ₂ CH ₂ OCH ₂ C ₆ H ₅ , -CH ₂ - £ jJ, n-CH ₂ -C ^with C ₇ H ₁₅ , CH ₂ CH ₂ OCH ₃ , CH ₂ CH = CH ₂ , - £ H-CH = CH ₂ , CH ₂ -C = CH ₂ . CH-CHR-j and R ₂ each represent CH ₃ , CH (CH ₃ ) ₂ , C ₂ H ₅ ,, CH ₂ CH (CH ₃ ) ₂ , CHCH (CH ₃ ) ₂ , or together form - Jc ^ (CH ₂ ) J -, - (CH ₂ ) - or - (CH ₂ ) ₅ , A is V ^H 3 J nitrogen or CR ₃ where R _{3 is} hydrogen, X is H, CH ₃ , Cl, Y and Z are each hydrogen, methyl, OCF ₃ , CH ₂ F, SCH ₃ , CH ₂ = CH-CH ₂ O , C ₂ H ₅ , C ^, -0-C1, Br, -O-CH ,, OCH ₃ , C ₃ H ₇ , Cl, CF ₃ , OCH ^ -CH ^ CH ^ OCgH ^ N (CH ₃ ) ₂ , -OCH ₂ CH = CH ₂ , -OCH ₂ C = CH, -OCHF ₂ , or else form - (CH ^ -, - (CH ^ -, or O where B is 0 or S, W is O or S , characterized in that B _, _ which reduces the compound of the formula: 232 - wherein X, Y, Z, A, R, R, j, R ₂ and W are predefined, using sodium cyanoborohydride, in a solvent such as methanol, at room temperature and in the pH range from about 2 to about 5 . AMERICAN CYANAMID COMPANY Authorized Agent, The present invention includes a process for the preparation of imidazolidinone and the imidazolidinone formula; ABSTRACT P-1336/84 1312-A-246 Hours 29,434 CH ₂ -C (C1) = CH ₂ , C ₆ H ₁₃ , CH (CH ₃ ) CH = CH-CH ₃ , CH ₂ CH = (CH ₃ ) ₂ , CH ₂ = CCH ₂ OH, c (ch ₃ ) csch, ch ₂ ch ₂ n® (ch ₃ ), 1®, -C (CH ₃ > ₃ , -θ, C h ₃₇ , -c ₄ h ₉ , ch ₂ -ch = ch-c ₇ h ₁₅ , - c ₁₂ h ₂₅ , ch ₂ ch ₂ ock ₂ c ₆ h ₅ , -ch ₂ -Q, -CH ₂ -C3C ₇ H _i5 ,, CH ₂ CH ₂ OCH ₃ , CH ₂ CH = CH ₂ , -CH-CH = CH ₂ , CH ₂ -J = CH ₂ , R ₁ and R ₂ each pre- * place CH ₃ , CH ₁ CH ^, C ^ H. ., -Ζλ, CH ₂ CH (CH ₃ ) ₂ , CHCHiCH ^, or together form - ^ H- (CH ₂ ) ^ J-, - (CH ₂ ) - or - (CH ₂ ) ₅ , A is nitrogen or CR ₃ where P. is hydrogen, X is H, CH ₃ , Cl, Y and 7. are each hydrogen, methyl, ocf ₃ , ch ₂ f, sch ₃ , ch ₂ = ch-ch ₂ o, c ₂ h ₅ , cf ₃ , c ₄ h ₉ , ^ θ-ci; Br, Ηθ-CH ^ OCH ₃ , C ₃ H _? , Cl, C _g H ₅ , CF ₃ , OCH ₂ -, CH = CH ₂ , ΟΟθΗ ^, NiCH ^, -OCH ₂ CH = CH _2> -OCH ₂ C = CH, -OCHF ₂ , OCH _3, or together form - (CH ^ - or. - (CH ^ -, and W is 0 or S, The novelty of the process is in friction. with sodium cyanoborohydride, in methanol, at room temperature.